Thiazolyl inhibitors of Tec family tyrosine kinases

ABSTRACT

Novel thiazolyl compounds and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of Tec family tyrosine kinase-associated disorders such as cancer, immunologic disorders and allergic disorders.

[0001] This application claims priority to U.S. Provisional ApplicationSerial No. 60/257,830 filed Dec. 21, 2000, the entirety of which isincorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention provides for thiazolyl compounds useful asinhibitors of Tec family tyrosine kinases (especially inhibitors of Emt)and to pharmaceutical compositions containing such compounds. Thepresent invention further provides for methods of using such compoundsas immunosuppressive, anti-inflammatory, anti-allergic, and anti-canceragents.

BACKGROUND OF THE INVENTION

[0003] The present invention relates to inhibitors of the Tec familytyrosine kinases, and particularly, inhibitors of Emt. The Tec familykinases include Emt [expressed mainly in T cells; Gibson, S. et al.,Blood 82, 1561-1572 (1993) ], Txk [T-cell expressed kinase; Haire, R. N.et al., Hum. Mol. Genet. 3, 897-901 (1994)], Tec [tyrosine kinaseexpressed in hepatocellular carcinoma cells; Mano et al., Oncogene 5,1781-1786 (1990)], Btk [Bruton's tyrosine kinase; Vetrie, D. et al.,Nature 361, 226-233, (1993)], and Bmx [bone marrow kinase, X-linked;Tamagnon, L. et al., Oncogene 9, 3683-3688 (1994)].

[0004] Mammalian immunity relies on the activation of T cells uponantigen presentation. The molecular mechanisms of T cell activation areinitiated by the sequential activation of three distinct classes ofnon-receptor protein tyrosine kinases (PTK) following the engagement ofthe T cell antigen receptor (TCR). These three classes of PTK are theSrc family kinases (Lck and Lyn), the Syk family kinases (ZAP-70 andSyk), and the Tec family kinases (Emt, Txk, and Tec). Inhibition of oneor more of these kinases will impede the initiation signals and block Tcell activation following antigen presentation. Thus, small molecularweight inhibitors of these kinases can be applied to treat the diseasesthat are associated with unwanted T cell activation.

[0005] Emt, also known as Itk (Interleukin-2-inducible T cell kinases)or Tsk (T-cell-specific tyrosine kinase), is expressed solely in T,natural killer, and mast cells. Emt is tyrosine-phosphorylated andactivated in response to cross-linking of TCR, CD28, or CD2; and hasbeen implicated in thymocyte development and the activation of T cellsthrough TCR and CD28 engagement. Inside the cells, Emt is regulated bymembrane recruitment followed by Lck phosphorylation andautophosphorylation. Emt is recruited to the membrane rafts for Lckphosphorylation through the interaction between the pleckstrin homology(PH) domain of Emt and the membrane lipid, phosphotidylinositol(3,4,5)-triphosphate [Bunnell et al., J. Biol. Chem. 275, 2219-2230(2000)].

[0006] Gene knockout studies reveal that mice lacking Emt have decreasednumbers of mature thymocytes, especially CD4+T cells. The T cellsisolated from such mice are compromised in their proliferative responseto allogeneic MHC stimulation, and to anti-TCR/CD3 cross-linking [LiaoX. C. and Littman, D. R., Immunity 3, 757-769 (1995)]. These T cellsalso exhibit defective PLCγ1 tyrosine phosphorylation, inositoltriphosphate production, Ca²⁺ moblization, and cytokine production (suchas IL-2 and IFNγ) in response to TCR cross-linking [Schaeffer, E. M. etal., Science 284, 638-641 (1999)]. This genetic evidence indicates thatEmt activity plays a requisite role in TCR signal transduction; andselective inhibition of Emt should have immunosuppressive,anti-inflammatory, and anti-proliferative effects. In addition,Emt-deficient mice are unable to establish functional Th2 cells (theIL-4 producing cells) and such mice are unable to clear parasiticinfections depending upon a Th2 response [Fowell, D. J. et al., Immunity11, 399-409 (1999)]. This observation also suggests that Emt may be anattractive target for modulating dysregulated allergic pathways mediatedby Th2 cells.

SUMMARY OF THE INVENTION

[0007] The present invention provides thiazolyl compounds of thefollowing formula I and salts thereof for use as Emt tyrosine kinaseinhibitors:

[0008] where

[0009] Q₁ is thiazolyl;

[0010] Q₂ is aryl or heteroaryl optionally independently substitutedwith one or more (preferably one to three) substituents R_(1a);

[0011] Z is

[0012] (1) —O—,

[0013] (2) —S—,

[0014] (3) —NR₄—,

[0015] (4) —CR₄R₅—,

[0016] (5) —CR₄R₅—O—CR_(4a)R_(5a)—,

[0017] (6) —CR₄R₅—NR_(4b)—CR_(4a)R_(5a)—,

[0018] (7) —CR₄R₅—S—CR_(4a)R_(5a)—,

[0019] (8) —CR₄R₅—O—,

[0020] (9) —O—CR₄R₅—,

[0021] (10) —CR₄R₅—NR_(4b)—,

[0022] ( 11) —NR_(4b)—CR₄R₅—,

[0023] (12) —CR₄R₅—S—,

[0024] (13) —S—CR₄R₅—,

[0025] (14) —S(O)_(q)— where q is 1 or 2,

[0026] (15) —CR₄R₅—S(O)_(q)—, or

[0027] (16) —S(O)_(q)—CR₄R₅—;

[0028] R₁ and R_(1a) are independently

[0029] (1) hydrogen or R₆,

[0030] (2) —OH or —OR₆,

[0031] (3) —SH or —SR₆,

[0032] (4) —C(O)_(q)H, —C(O)_(q)R₆, or —O—C(O)_(q)R₆,

[0033] (5) —SO₃H or —S(O)_(q)R₆,

[0034] (6) halo,

[0035] (7) cyano,

[0036] (8) nitro,

[0037] (9) —Z₄—NR₇R₈,

[0038] (10) —Z₄—N(R₉)—Z₅—NR₁₀R₁₁,

[0039] (11) —Z₄—N(R₁₂)—Z₅—R₆, or

[0040] (12) —P(O)(OR₆)₂;

[0041] R₂ and R₃ are each independently H, —Z₄—R_(6a), or—Z₄—NR_(7a)R_(8a)

[0042] R₄, R_(4a), R_(4b), R₅ and R_(5a) are each independentlyhydrogen, alkyl, aryl, aralkyl, cycloalkyl, or heteroarylalkyl;

[0043] R₆, R_(6a), R_(6b) and R_(6c) are independently alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl,aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which isunsubstituted or substituted with Z₁, Z₂ and one or more (preferably,one or two) groups Z₃,

[0044] R₇, R_(7a), R₈, R_(8a), R₉, R₁₀, R₁₁ and R₁₂

[0045] (1) are each independently hydrogen, or —Z₄R_(6b); or

[0046] (2) R₇ and R₈, or R_(7a) and R_(8a) may together be alkylene,alkenylene, or heteroalkylene, completing a 3- to 8-membered saturatedor unsaturated ring with the nitrogen atom to which they are attached,which ring is unsubstituted or substituted with Z₁, Z₂ and one or moregroups Z₃, or

[0047] (3) any two of R₉, R₁₀ and R₁₁ may together be alkylene,alkenylene or heteroalkylene completing a 3- to 8-membered saturated orunsaturated ring together with the nitrogen atoms to which they areattached, which ring is unsubstituted or substituted with one or moreZ₁, Z₂ and Z₃;

[0048] Z₁, Z₂ and Z₃ are each independently

[0049] (1) hydrogen or Z₆,

[0050] (2) —OH or —OZ₆,

[0051] (3) —SH or —SZ₆,

[0052] (4) —C(O)_(q)H, —C(O)_(q)Z₆, or —O—C(O)_(q)Z₆,

[0053] (5) —SO₃H, —S(O)_(q)Z₆, or S(O)_(q)N(Z₉)Z₆,

[0054] (6) halo,

[0055] (7) cyano,

[0056] (8) nitro,

[0057] (9) —Z₄—NZ₇Z₈,

[0058] (10) —Z₄—N(Z₉)—Z₅—NZ₇Z₈,

[0059] (11) —Z₄—N(Z₁₀)—Z₅—Z₆,

[0060] (12) —Z₄—N(Z₁₀)—Z₅—H,

[0061] (13) oxo,

[0062] (14) any two of Z₁, Z₂, and Z₃ on a given substituent maytogether be alkylene or alkenylene completing a 3- to 8-memberedsaturated or unsaturated ring together with the atoms to which they areattached; or

[0063] (15) any two of Z₁, Z₂, and Z₃ on a given substituent maytogether be —O—(CH₂)_(q)—O—;

[0064] Z₄ and Z₅ are each independently

[0065] (1) a single bond,

[0066] (2) —Z₁₁—S(O)_(q)—Z₁₂—,

[0067] (3) —Z₁₁—C(O)—Z₁₂—,

[0068] (4) —Z₁₁—C(S)—Z₁₂—,

[0069] (5) —Z₁₁—O—Z₁₂—,

[0070] (6) —Z₁₁—S—Z₁₂—,

[0071] (7) —Z₁₁—O—C(O)—Z₁₂—,

[0072] (8) —Z₁₁—C(O)—O—Z₁₂—; or

[0073] (9) alkyl

[0074] Z₆ and Z_(6a) are independently

[0075] (i) alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl,aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;

[0076] (ii) a group (i) which is itself substituted by one or more ofthe same or different groups (i); or

[0077] (iii) a group (i) or (ii) which is independently substituted byone or more (preferably 1 to 3) of the groups (2) to (15) of thedefinition of Z₁;

[0078] Z₇, Z₈, Z₉ and Z₁₀

[0079] (1) are each independently hydrogen or —Z₄—Z_(6a);

[0080] (2) Z₇ and Z₈ may together be alkylene, alkenylene, orheteroalkylene completing a 3- to 8-membered saturated or unsaturatedring together with the atoms to which they are attached, which ring isunsubstituted or substituted with one or more Z₁, Z₂ and Z₃, or

[0081] (3) Z₇ or Z₈, together with Z₉, may be alkylene, alkenylene, orheteroalkylene completing a 3- to 8-membered saturated or unsaturatedring together with the nitrogen atoms to which they are attached, whichring is unsubstituted or substituted with one or more Z₁, Z₂ and Z₃;

[0082] Z₁₁ and Z₁₂ are each independently

[0083] (1) a single bond,

[0084] (2) alkylene,

[0085] (3) alkenylene, or

[0086] (4) alkynylene.

DETAILED DESCRIPTION OF THE INVENTION

[0087] The following are definitions of terms used in thisspecification. The initial definition provided for a group or termherein applies to that group or term throughout the presentspecification, individually or as part of another group, unlessotherwise indicated.

[0088] The terms “alk” or “alkyl” refer to straight or branched chainhydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbonatoms. The expression “lower alkyl” refers to alkyl groups of 1 to 4carbon atoms.

[0089] The term “alkenyl” refers to straight or branched chainhydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having atleast one double bond. Where an alkenyl group is bonded to a nitrogenatom, it is preferred that such group not be bonded directly through acarbon bearing a double bond.

[0090] The term “alkynyl” refers to straight or branched chainhydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having atleast one triple bond. Where an alkynyl group is bonded to a nitrogenatom, it is preferred that such group not be bonded directly through acarbon bearing a triple bond.

[0091] The term “alkylene” refers to a straight chain bridge of 1 to 5carbon atoms connected by single bonds (e.g., —(CH₂)_(x)— wherein x is 1to 5), which may be substituted with 1 to 3 lower alkyl groups.

[0092] The term “alkenylene” refers to a straight chain bridge of 2 to 5carbon atoms having one or two double bonds that is connected by singlebonds and may be substituted with 1 to 3 lower alkyl groups. Exemplaryalkenylene groups are —CH═CH—CH═CH—, —CH₂—CH═CH—, —CH₂—CH═CH—CH₂—,—C(CH₃)₂CH═CH— and —CH(C₂H₅)—CH═CH—.

[0093] The term “alkynylene” refers to a straight chain bridge of 2 to 5carbon atoms that has a triple bond therein, is connected by singlebonds, and may be substituted with 1 to 3 lower alkyl groups. Exemplaryalkynylene groups are —C≡C—, —CH₂—C≡C—, —CH(CH₃)—C≡C— and —C≡C—CH(C₂H₅)CH₂—.

[0094] The term “heteroalkylene” refers to alkylene or alkenylene groupscontaining one or more heteroatoms N, O or S.

[0095] The terms “ar” or “aryl” refer to aromatic cyclic groups (forexample 6 membered monocyclic, 10 membered bicyclic or 14 memberedtricyclic ring systems) which contain 6 to 14 carbon atoms. Exemplaryaryl groups include phenyl, naphthyl, biphenyl and anthracene.

[0096] The terms “cycloalkyl” refers to saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl andtricyclicalkyl, containing a total of 3 to 20 carbons forming the rings,preferably 3 to 7 carbons, forming the ring and which may be fused to 1or 2 aromatic or heterocyclo rings, which include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclodecyl, cyclododecyl, cyclohexenyl,

[0097] The terms “halogen” and “halo” refer to fluorine, chlorine,bromine and iodine.

[0098] The terms “heterocycle”, “heterocyclic” or “heterocycle” refer tofully saturated or unsaturated, including aromatic (i.e. “heteroaryl”)cyclic groups, for example, 4 to 7 membered monocyclic, 7 to 11 memberedbicyclic, or 10 to 15 membered tricyclic ring systems, which have atleast one heteroatom in at least one carbon atom-containing ring. Eachring of the heterocyclic group containing a heteroatom may have 1, 2, 3or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/orsulfur atoms, where the nitrogen and sulfur heteroatoms may optionallybe oxidized and the nitrogen heteroatoms may optionally be quaternized.The heterocyclic group may be attached at any heteroatom or carbon atomof the ring or ring system.

[0099] Exemplary monocyclic heterocyclic groups include pyrrolidinyl,pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, 5-tetrazolyl,

[0100] and the like.

[0101] Exemplary bicyclic heterocyclic groups include indolyl,benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl,quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl,pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl) or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl

[0102] and the like.

[0103] Exemplary tricyclic heterocyclic groups include carbazolyl,benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl andthe like.

[0104] The term “heteroaryl” refers to a 5- or 6-membered aromatic ringwhich includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen orsulfur, and such rings fused to an aryl, cycloalkyl, or heterocyclo ring(e.g. benzothiophenyl, indolyl), and includes possible N-oxides, such as

[0105] and the like.

[0106] Where q is 1 or 2, “—C(O)_(q)H” denotes —C(O)—H or —C(O)—OH;“—C(O)_(q)R₆” or “—C(O)_(q)Z₆” denote, respectively, —C(O)—R₆ or—C(O)—OR₆, or —C(O)—Z₆ or —C(O)—OZ₆; “—O—C(O)_(q)R₆” or “—O—C(O)_(q)Z₆”denote, respectively, —O—C(O)—R₆ or —O—C(O)—OR₆, or —O—C(O)—Z₆ or—O—C(O)—OZ₆; and “—S(O)_(q)R₆” or “—S(O)_(q)Z₆” denote, respectively,—SO—R₆ or —SO₂—R₆, or —SO—Z₆ or —SO₂—Z₆.

[0107] Compounds of the formula I may in some cases form salts which arealso within the scope of this invention. Reference to a compound of theformula I herein is understood to include reference to salts thereof,unless otherwise indicated. The term “salt(s)”, as employed herein,denotes acidic and/or basic salts formed with inorganic and/or organicacids and bases. Zwitterions (internal or inner salts) are includedwithin the term “salt(s)” as used herein (and may be formed, forexample, where the R substituents comprise an acid moiety such as acarboxyl group). Also included herein are quaternary ammonium salts suchas alkylammonium salts. Pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salts are preferred, although other saltsare useful, for example, in isolation or purification steps which may beemployed during preparation. Salts of the compounds of the formula I maybe formed, for example, by reacting a compound I with an amount of acidor base, such as an equivalent amount, in a medium such as one in whichthe salt precipitates or in an aqueous medium followed bylyophilization.

[0108] Exemplary acid addition salts include acetates (such as thoseformed with acetic acid or trihaloacetic acid, for example,trifluoroacetic acid), adipates, alginates, ascorbates, aspartates,benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates,hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates,lactates, maleates, methanesulfonates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, sulfates (such as those formed with sulfuricacid), sulfonates (such as those mentioned herein), tartrates,thiocyanates, toluenesulfonates, undecanoates, and the like.

[0109] Exemplary basic salts (formed, for example, where the Rsubstituents comprise an acidic moiety such as a carboxyl group) includeammonium salts, alkali metal salts such as sodium, lithium, andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases (for example, organic amines)such as benzathines, dicyclohexylamines, hydrabamines,N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. The basicnitrogen-containing groups may be quaternized with agents such as loweralkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromidesand iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, anddiamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl andstearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyland phenethyl bromides), and others.

[0110] Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound which, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound of theformula I, or a salt and/or solvate thereof. Solvates of the compoundsof formula I are preferably hydrates.

[0111] All stereoisomers of the present compounds, such as those whichmay exist due to asymmetric carbons on the R substituents of thecompound of the formula I, including enantiomeric and diastereomericforms, are contemplated within the scope of this invention. Individualstereoisomers of the compounds of the invention may, for example, besubstantially free of other isomers, or may be admixed, for example, asracemates or with all other, or other selected, stereoisomers. Thechiral centers of the present invention can have the S or Rconfiguration as defined by the IUPAC 1974 Recommendations.

[0112] Throughout the specification, groups and substituents thereof arechosen to provide stable moieties and compounds.

[0113] Preferred compounds within the scope of the formula I includethose wherein:

[0114] Q₂ is phenyl optionally substituted with one or more groups asdefined in R_(1a) (especially, alkyl, hydroxy, alkoxy, haloalkoxy, halo,nitro, —C(O)_(q)R₆, —C(O)_(q)H, —Z₄—NR₇R₈, —Z₄—N(R₁₂)—Z₅—Z₆, or—Z₄—N(R₉)—Z₅—NR₁₀R₁₁);

[0115] Z is selected from —S—, —CR₄R₅—S—, —S—CR₄R₅—,—CR₄R5—O—CR_(4a)R_(5a)—, —CR₄R₅—NR⁴—CR_(4a)R_(5a)—, —CR₄R₅—, —CR₄R₅—SO₂—or —CR₄R₅—S(O)—;

[0116] R₁ is hydrogen;

[0117] R₂ is hydrogen or alkyl; and

[0118] R₃ is H, —Z₄R_(6a) or —Z₄NR_(7a)R_(8a).

[0119] More preferred compounds within the scope of formula I includethose wherein:

[0120] Q₂ is phenyl optionally substituted with one or more groupsselected from alkyl, alkoxy, hydroxy, —C(O)R₆ (especially wherein R₆ isoptionally substituted alkyl or heterocyclo (especially piperazinyl),—C(O)NR₇R₈ or —NR₇R₈;

[0121] Z is selected from —CR₄R₅—O—CR_(4a)R_(5a)—, —S—, —CR₄R₅—S— or—S—CR₄R₅—;

[0122] R₁ is hydrogen;

[0123] R₂ is hydrogen or alkyl; and

[0124] R₃ is —Z₄R_(6a), especially where:

[0125] (a) Z₄ is a single bond and R_(6a) is optionally substitutedheteroaryl (preferably pyridinyl, pyrimidinyl, or quinolinyl optionallysubstituted with one or more Z₁, Z₂ or Z₃ which are preferably alkyl,hydroxyalkyl, halo, —Z₄—NZ₇Z₈, —C(O)_(q)H, —C(O)_(q)Z₆, —OZ₄ orheterocyclo)

[0126] (b) Z₄ is —C(O)— and R_(6a) is

[0127] (1) aryl (especially phenyl) optionally substituted with one ormore Z₁, Z₂ or Z₃ (preferably —Z₄—NZ₇Z₈, —OZ_(a), hydroxy, heterocyclo,or alkyl which may be optionally substituted with any of the precedingpreferred Z₁, Z₂ or Z₃ groups) (where present, at least one substituentis preferably in the para position);

[0128] (2) alkyl optionally substituted with one or more Z₁, Z₂ or Z₃;

[0129] (3) cycloalkyl (especially cyclopropyl) optionally substitutedwith one or more Z₁, Z₂ or Z₃ (especially aryl, aralkyl, halo, hydroxy,—C(O)_(q)H, —C(O)_(q)Z₆ or alkyl optionally substituted with hydroxy,—OZ₆ or —Z₄—NZ₇Z₈)); or

[0130] (4) heterocyclo (especially pyrrolidinyl, piperidyl, piperidenyl,piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl or pyrimidinyl)optionally substituted with one or more Z₁, Z₂ or Z₃ (especially—Z₄—NZ₇Z₈, —C(O)_(q)H, —C(O)_(q)Z₆, or alkyl optionally substituted withhydroxy, —OZ₆ or —Z₄—NZ₇Z₈); or

[0131] (c) Z₄ is —C(O)—O— and R_(6a) is alkyl, cycloalkyl, aryl oraralkyl, any of which may be optionally substituted with one or more Z₁,Z₂ or Z₃.

[0132] Preferred compounds within the scope of formula I includecompounds of the following formula II:

[0133] where Z, Q₂, R₁, R₂ and R₃ are as described above (including thedescription of preferred substituents). Additionally, preferredcompounds within the scope of formula II include compounds of thefollowing formulae IIIa, II.B and IIIc:

[0134] where

[0135] Z is as described above (preferably —S—, —CR₄R₅—S—, or —S—CR₄R₅—where R₄ and R₅ are H);

[0136] R₁ is as described above (preferably H);

[0137] R₂ and R₃ are as described above (including the description ofpreferred substituents);

[0138] R_(1aa) is —C(O)_(q)H, —C(O)_(q)R₆, —Z₄—NR₇R₈,—Z₄—N(R₉)—Z₅—NR₁₀R₁₁ or —Z₄—N(R₉)—Z₅—R₆; and

[0139] R_(1ab), R_(1ac) and R_(1ad) are independently selected from anyR₁ group (especially, H, alkyl, hydroxy, nitro, halo, —OR₆, —NR₇R₈,—C(O)_(q)H or —C(O)_(q)R₆).

[0140] Preferred compounds within the scope of formulae III includecompounds of the following formula IV

[0141] where

[0142] Z, R₁, R_(1aa), R₂, and R₃ are as described above; and

[0143] One of R_(1ab), R_(1ac) and R_(1ad) is H and the other two areindependently alkyl, alkoxy, haloalkoxy, hydroxy, nitro, halo, —NR₇R₈,—C(O)_(q)H or —C(O)_(q)R₆) (preferably alkyl or alkoxy). (preferably,R_(1c) is H when Z is —S—, and R_(1d) is H when Z is —S—CR₄R₅— or—O—CR₄R₅—);

[0144] Compounds within the scope of formula IV include compounds of thefollowing formula V:

[0145] where

[0146] Z, R₁, R_(1ab), R_(1ac), R_(1ad), R₂ and R₃ are described forformula IV;

[0147] X₁ is C or N (preferably N);

[0148] X₂ is CZ_(3a), NZ_(3a), O or S (preferably CZ_(3a), NZ_(3a) or O)(more preferably NZ_(3a));

[0149] Z₁ and Z₂ are as described for formula I (preferably H);

[0150] Z_(3a) is H, hydroxy, optionally substituted alkyl (especiallyoptionally substituted with hydroxy, cyano, aryl, —OZ₆, —Z₄—NZ₇Z₈,—C(O)_(q)H or —C(O)_(q)Z₆), optionally substituted heterocyclo(preferably optionally substituted piperidinyl, tetrazolyl, pyridinyl,pyrimidinyl, or pyrrazolyl), optionally substituted aryl or aralkyl(especially optionally substituted with halo), —OZ₆, —C(O)_(q)H,—C(O)_(q)Z_(6a), —Z₄—NZ₇Z₈ (especially where Z₄ is a bond or —C(O)—), or—Z₄—N(Z₁₀)—Z₅—Z₆ (especially where Z₄ is a bond or —C(O)— and Z₅ is —O—,—SO₂—, or —C(O)O—);

[0151] n is 1 to 3; and

[0152] m is zero to 2.

[0153] Methods of Preparation

[0154] The compounds of the formula I may be prepared by methods such asthose illustrated in the following Schemes A through C and I throughVIII. Solvents, temperatures, pressures, and other reaction conditionsmay readily be selected by one of ordinary skill in the art. Alldocuments cited are incorporated herein by reference in their entirety.Starting materials are commercially available or readily prepared by oneof ordinary skill in the art. Constituents of compounds are as definedelsewhere in the specification or as specifically defined in a scheme.

[0155] The methods described herein may be carried out with startingmaterials and/or reagents in solution or alternatively, whereappropriate, with one or more starting materials or reagents bound to asolid support (see (1) Thompson, L. A., Ellman, J. A., Chemical Reviews,96, 555-600 (1996); (2) Terrett, N. K., Gardner, M., Gordon, D. W.,Kobylecki, R. J., Steele, J., Tetrahedron, 51, 8135-8173 (1995); (3)Gallop, M. A., Barrett, R. W., Dower, W. J., Fodor, S. P. A., Gordon, E.M., Journal of Medicinal Chemistry, 37, 1233-1251 (1994); (4) Gordon, E.M., Barrett, R. W., Dower, W. J., Fodor, S. P. A., Gallop, M. A.,Journal of Medicinal Chemistry, 37, 1385-1401 (1994); (5) Balkenhohl,F., von dem Bussche-Hüinnefeld, Lansky, A., Zechel, C., AngewandteChemie International Edition in English, 35, 2288-2337 (1996); (6)Balkenhohl, F., von dem Bussche-Hüinnefeld, Lansky, A., Zechel, C.,Angewandte Chemie, 108, 2436-2487 (1996); and (7) Sofia, M. J., DrugsDiscovery Today, 1, 27-34 (1996)).

[0156] Compounds of formula I that contain chiral centers maybe obtainedin non-racemic form by non-racemic synthesis or resolution by methodswell known to those skilled in the art. Compounds that are non-racemicare designated as “chiral” in the examples.

[0157] In the examples described below it may be necessary to protectreactive functionality such as hydroxy, amino, thio or carboxy groups,where these are desired in the final product, to avoid their unwantedparticipation in reactions. The introduction and removal of protectinggroups are well known to those skilled in the art, for example see(Green, T. W. in “Protective Groups in Organic Synthesis”, John Wileyand Sons, 1991).

[0158] Scheme A illustrates a general method for forming compound Iawhich is a compound of formula I where Z═O, S, or NR₄. Compound Ia canbe formed by reacting compound i with compound ii in the presence of anorganic or inorganic base e.g. alkalimetal alkoxide, alkyl or aryllithium, or Grignard reagent in a protic or aprotic solvent e.g.tetrahydrofuran, ether, methyl alcohol, ethanol or dimethyl formamide ata temperature of 78° C. to 100° C.

[0159] Scheme B illustrates a general method for forming compound Iawhich is a compound of formula I where Z═O, S, NR₄. Compound Ia can beformed by reacting compound iii with compound iv in presence of anorganic or inorganic base e.g. alkali metal alkoxide, alkalimetalhydride, alkyl or aryl lithium or Grignard reagent in a protic or aprotic solvent e.g. THF, ether, methanol, ethanol or DMF at atemperature of −78° C. to 100° C.

[0160] Scheme C illustrates a general method for forming Compound Ibwhich is a compound of formula I where Z═CR₄R₅. Compound Ib can beformed by reacting Compound v with an organometallic reagent e.g. alkylor aryl lithium or cuprate or Grignard reagent and then reacting withCompound vi in an aprotic solvent e.g. ether, THF, DMF at a temperatureof −78° C. to 60° C.

[0161] Methods for preparing preferred examples of compound I areillustrated in Schemes I to IX.

[0162] As shown in Scheme I, amine Ic which can be formed by methodsdescribed in Schemes A, B or C can be reacted with a chloroformate 1 ordicarbonate 2 to form Id. Compound Id can be treated with a base such assodium hydride, sodium/potassium hexamethyl disilazide, or lithiumdiisopropylamide (LDA), and an alkylating agent R₂X where X is halogenand R₂ is preferably alkyl, arylalkyl or cycloalkylalkyl to formCompound Ie.

[0163] Scheme II illustrates methods which may be used for thepreparation of Compounds Ig, Ih, Ii, Ij and Ik which are compounds offormula I where R₂ is any group as defined, R₃ is an acyl or thioacyl, Zis not —NH and R₁ is not a primary or secondary amine. Ig, Ih, Ii, Ijand Ik have other particular substituents which are specified in thisScheme and below. The starting compound If can be prepared by suitablemethods described in Schemes A, B or C.

[0164] Amide Ig can be prepared by treatment of amine If with acarboxylic acid 3 in the presence of reagents which activate thecarboxyl group for reaction as described above, for example BOP reagent,HATU and carbodiimides such as DCC or EDCI either alone or incombination with a hydroxybenzotriazole. Alternatively, the alidhalide 4may be reacted with amine compound If in presence of an acid scavengersuch as pyridine ordiisopropyl ethyl amine. The corresponding thioamideIh can be prepared by treatment of amide Ig with Lawesson's reagent asdescribed above. Carbamate Ii can be prepared by treatment of aminecompound If with a chloroformate 1 or dicarbonate 2 in the presence ofan acid scavenger such as diisopropylethylamine, triethylamine or anaqueous inorganic base such as sodium/potassium bicarbonate,sodium/potassium carbonate or hydroxide.

[0165] The urea Ij may be prepared by treatment of amine compound Ifwith either: 1) a chloroformate 1, such as phenyl chloroformate,followed by reaction with an amine 5; 2) a carbamoyl chloride 6 inpresence of an acid scavenger such as diisopropylethylamine; or 3)reaction with an isocyanate 7a (where R_(c) in Ii═H). The correspondingthiourea Ik may be prepared by treatment of amine compound Ie with aisothiocyanate 7b.

[0166] Ra is selected from those groups included in the definition ofR_(6a) such that the group —C(═A)—R_(a) is an acyl group within thedefinition of R₃. Rb and Rc are selected from those groups included inthe definitions of R_(7a) and R_(8a), such that the group—C(═A)—N(Rb)(Rc) is an acyl or thioacyl group within the definition ofR₃.

[0167] Scheme II illustrates a method which can be used for thepreparation of Il, which is a compound of formula I where R₂ is anygroup as defined other than acyl, and which is selected such that thenitrogen to which it is attached is basic, R3 is alkyl, cycloalkyl,cycloalkyl-alkyl, cycloalkenylalkyl, aralkyl or saturated heterocycleand Z is not —NH. The starting compounds Ik and Ic can be prepared bysuitable methods described in Schemes A, B and C. As shown in SchemeIII, amine compound Ik is reacted with an aldehyde or ketone 8 underreductive amination conditions described above to give the Compound Il.Compound Il may also be prepared by treatment of an amine compound Ic,where R₂ and R₃ are hydrogen, with t-butyl/t-amyl nitrite or sodiumnitrite and an acid such as HCl, H₂SO₄ in presence of a copper (II)halide to give the halo compound vii, followed by displacement withamine 9 in the presence or absence of a base such as sodium or potassiumhydride or the like (see Lee et al., J. Heterocyclic Chemistry22,1621,1985). Rd and Re are independently selected from hydrogen,alkyl, aryl, cycloalkyl or cycloalkenyl or together are alkylene oralkenylene completing a 3- to 8-membered saturated or unsaturated ring,such that the group —CH(Rd)(Re) is a group within the definition of R.

[0168] As shown in Scheme IV, when R₂ is any group as defined other thanacyl, and is selected such that the nitrogen to which it is attached isbasic, R₃ is an aryl or heteroaryl, amine compound Ik may be reactedwith a halophenyl or haloheteroaromatic group 10 in the presence of aPd(0)catalyst (See J. Am. Chem. Soc. 118, 7215, 1996) to give amine Il,which is a compound of formula I having the particular substituentsdescribed in this Scheme. The starting compound Il can be prepared bysuitable methods described in Scheme A, B or C.

[0169] As shown in Scheme V, when R₂ is any group as defined, R₃ is aheteroaromatic group, amine compound, Im may be reacted, in the presenceof a base if needed, with a 2-halo-substituted heteroaromatic compound11 where Q_(a), together with atoms to which it is bonded, forms a 5- or6-membered monocyclic or 10- to 12-membered bicyclic heteroaromaticgroup (such as forming 2-chloropyridine, 2-chloropyrimidine or2-chloroquinoline) to give the amine compound In, where In is a compoundof formula I having the particular substituents described in thisscheme. The starting compound Im can be prepared by suitable methodsdescribed in Schemes A, B and C.

[0170] As shown in Scheme VI, thiourea compound Io may be reacted withthe appropriate amine 12 in the presence of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP chloride), benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluoro-phosphate (BOP-reagent),[O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium]hexafluorophosphate(HATU) and a carbodiimide such as dicyclohexylcarbodiimide (DCC) or3-ethyl-e(dimethylamino) propyl carbodiimide (EDCI) ordiisopropylcarbodiimide (DIC) in the presence of an organic base such astriethylamine, diisopropylethylamine or dimethylaminopyridine insolvents such as dimethylformamide, dichloromethane or tetrahydrofuranto form compound Ip, which is a compound of formula I having theparticular substituents described in this scheme.

[0171] Alternatively, compound Io can be reacted with the appropriateamine 12 in the presence of a mercury (II) salt such as mercurychloride, or by other known methods in the literature, to form Ip. Thestarting material Io can be prepared by suitable methods described inSchemes A, B, or C or Scheme II.

[0172] As shown in Scheme VII, amine Iq can be reacted with diphenylcyanocarbonimidate 13 either alone or in the presence of a base such assodium hydride, sodium/potassium hexamethyldisilazide ordimethylaminopyridine in acetonitrile, tetrahydrofuran ordimethylformamide at room temperature or elevated temperature to formintermediate compound Ir which can be reacted with amine 14 to formcompound Is, which is a compound of formula I having the particularsubstituents described in this scheme. The starting material Iq can beprepared by suitable methods described in Schemes A, B or C.

[0173] As shown in Scheme VIII, compound Iq can be reacted with either15 or 16 either alone or in the presence of a base such as sodiumhydride, sodium/potassium hexamethyldisilazide or dimethylaminopyridinein dimethylformamide or tetrahydrofuran at room temperature or elevatedtemperature to form compounds It or Iu, respectively, which can bereacted separately with amine 14 at room temperature or elevatedtemperature to form compound Iv or Iw, respectively. Compounds Iv and Iware compounds of formula I having the particular substituents asdescribed in this scheme. The starting material Iq can be prepared bysuitable methods described in Schemes A, B or C.

[0174] As shown in Scheme IX, compound Ix may be reduced using, forexample, lithium aluminum hydride in tetrahydrofuran at a temperature of0-55° C., or reacted with alkyl or aryl metal derivatives, such as alkyllithium or Grignard reagents, in aprotic solvents such as diethyl etheror tetrahydrofuran, at a temperature of −78 to 100° C. to afford alcoholIy. Alcohol Iy may then be reacted with compound vi alone or in thepresence of organic or inorganic bases, such as sodium hydride, lithiumhexamethyldisilazide, or potassium t-butoxide and the like, in a solventsuch as dimethylformamide, and at a temperature of 0-100° C. to givecompound Iaa. Alternatively, the alcohol moiety of Iy may be transformedinto a leaving group via tosylation or conversion to a halide and thenreacted with compound 18 alone or in the presence of bases such assodium hydride in solvents such as tetrahydrofuran or dimethylformamideat a temperature from 0-100° C. to give compound Ibb.

[0175] Utility

[0176] The compounds of the present invention are immunosuppressive,anti-inflammatory, anti-allergic, and anti-cancer agents. The compoundsof the present invention inhibit Tec family tyrosine kinases (especiallyEmt) and are thus useful in the treatment, including prevention andtherapy, of Tec family tyrosine kinase-associated disorders, especiallyEmt-associated disorders. “Tec family tyrosine kinase-associateddisorders” are those disorders which result from aberrant Tec familytyrosine kinase activity, and/or which are alleviated by the inhibitionof one or more of these enzymes. Compounds within the scope of thepresent invention selectively inhibit Emt and are thus useful in thetreatment, including prevention and therapy, of a range of disordersassociated with the activation of Emt (e.g., inflammatory disorders,allergic disorders and cancer). In addition to Emt, the compounds of thepresent invention inhibit other Tec family kinases including Btk, Txk,Tec, and Bmx and are useful in the treatment of the disorders associatedwith the activation of these Tec family kinases. Such disorders areexemplified by, but are not limited to, transplant rejection;transplantation tolerance induction; arthritis including rheumatoidarthritis, psoriatic arthritis, and osteoarthritis; multiple sclerosis;chronic obstructive pulmonary disease (COPD) such as emphysema;inflammatory bowel diseases including ulcerative colitis and Crohn'sdisease; lupus (systemic lupus erythematosis); graft vs. host disease;T-cell mediated hypersensitivity diseases including contacthypersensitivity, delayed-type hypersensitivity, and gluten-sensitiveenteropathy (Celiac disease); psoriasis; contact dermatitis (includingthat due to poison ivy); Hashimoto's thyroiditis; Sjogren's syndrom;autoimmune hyperthyroidism such as Graves's disease; Addison's disease(autoimmune disease of the adrenal glands); autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome); autoimmunealopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism;Guillain-Barre syndrome; diabetes (both type I and type II); otherautoimmune diseases; cancers such as leukemias and lymphomas;glomerulonephritis; serum sickness; uticaria; allergic diseasesincluding respiratory allergies (asthma, hayfever, allergic rhinitis)and skin allergies; scleracierma; mycosis fungoides; acute inflammatoryresponses (such as acute respiratory distress syndrome andischemia/reperfusion injury); dermatomyositis; alopecia areata; chronicactinic dermatitis; eczema; Behcet's disease; Pustulosis palmoplanteris;Pyoderna gangrenum; Sezary's syndrom; atopic dermatitis; systemicschlerosis; and morphea.

[0177] In a particular embodiment, the compounds of the presentinvention are useful for the treatment of the aforementioned exemplarydisorders irrespective of their etiology, for example, for the treatmentof transplant rejection, rheumatoid arthritis, multiple sclerosis,chronic obstructive pulmonary disease, inflammatory bowel disease,lupus, graft vs. host disease, T-cell mediated hypersensitivity disease,psoriasis, Hashimoto's thyroiditis, Guillain-Barre syndrom, cancer,contact dermatitis, allergic disease such as allergic rhinitis, asthma,ischemic or reperfusion injury, or atopic dermatitis whether or notassociated with the Tec family tyrosine kinases.

[0178] The present invention also provides pharmaceutical compositionscomprising at least one of the compounds of the formula I capable oftreating a protein tyrosine kinase-associated disorder in an amounteffective therefor, and a pharmaceutically acceptable vehicle ordiluent. The compositions of the present invention may contain othertherapeutic agents as described below, and may be formulated, forexample, by employing conventional solid or liquid vehicles or diluents,as well as pharmaceutical additives of a type appropriate to the mode ofdesired administration (for example, excipients, binders, preservatives,stabilizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

[0179] The compounds of the formula I may be administered by anysuitable means, for example, orally, such as in the form of tablets,capsules, granules or powders; sublingually; buccally; parenterally,such as by subcutaneous, intravenous, intramuscular, or intrasternalinjection or infusion techniques (e.g., as sterile injectable aqueous ornon-aqueous solutions or suspensions); nasally such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents. The present compounds may, for example, be administered ina form suitable for immediate release or extended release. Immediaterelease or extended release may be achieved by the use of suitablepharmaceutical compositions comprising the present compounds, or,particularly in the case of extended release, by the use of devices suchas subcutaneous implants or osmotic pumps. The present compounds mayalso be administered liposomally.

[0180] Exemplary compositions for oral administration includesuspensions which may contain, for example, microcrystalline cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners orflavoring agents such as those known in the art; and immediate releasetablets which may contain, for example, microcrystalline cellulose,dicalcium phosphate, starch, magnesium stearate and/or lactose and/orother excipients, binders, extenders, disintegrants, diluents andlubricants such as those known in the art. The present compounds mayalso be delivered through the oral cavity by sublingual and/or buccaladministration. Molded tablets, compressed tablets or freeze-driedtablets are exemplary forms which may be used. Exemplary compositionsinclude those formulating the present compound(s) with fast dissolvingdiluents such as mannitol, lactose, sucrose and/or cyclodextrins. Alsoincluded in such formulations may be high molecular weight excipientssuch as celluloses (avicel) or polyethylene glycols (PEG). Suchformulations may also include an excipient to aid mucosal adhesion suchas hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose(HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydridecopolymer (e.g., Gantrez), and agents to control release such aspolyacrylic copolymer (e.g., Carbopol 934). Lubricants, glidants,flavors, coloring agents and stabilizers may also be added for ease offabrication and use.

[0181] Exemplary compositions for nasal aerosol or inhalationadministration include solutions in saline which may contain, forexample, benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, and/or other solubilizing ordispersing agents such as those known in the art.

[0182] Exemplary compositions for parenteral administration includeinjectable solutions or suspensions which may contain, for example,suitable non-toxic, parenterally acceptable diluents or solvents, suchas mannitol, 1,3-butanediol, water, Ringer's solution, an isotonicsodium chloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

[0183] Exemplary compositions for rectal administration includesuppositories which may contain, for example, a suitable non-irritatingexcipient, such as cocoa butter, synthetic glyceride esters orpolyethylene glycols, which are solid at ordinary temperatures, butliquify and/or dissolve in the rectal cavity to release the drug.

[0184] Exemplary compositions for topical administration include atopical carrier such as Plastibase (mineral oil gelled with polyethyleneglycol).

[0185] The effective amount of a compound of the present invention maybe determined by one of ordinary skill in the art, and includesexemplary dosage amounts for an adult human of from about 0.1 to 100mg/kg of body weight of active compound per day, which may beadministered in a single dose or in the form of individual divideddoses, such as from 1 to 4 times per day. It will be understood that thespecific dose level and frequency of dosage for any particular subjectmay be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the species, age, body weight,general health, sex and diet of the subject, the mode and time ofadministration, rate of excretion, drug combination, and severity of theparticular condition. Preferred subjects for treatment include animals,most preferably mammalian species such as humans, and domestic animalssuch as dogs, cats and the like, subject to protein tyrosinekinase-associated disorders.

[0186] The compounds of the present invention may be employed alone orin combination with each other and/or other suitable therapeutic agentsuseful in the treatment of Tec family tyrosine kinase-associateddisorders such as Emt inhibitors other than those of the presentinvention, antiinflammatories, antiproliferatives, chemotherapeuticagents, immunosuppressants, anticancer agents and cytotoxic agents.

[0187] Exemplary such other therapeutic agents include the following:protein tyrosine kinase inhibitors (such as those disclosed in WO00/62778), cyclosporins (e.g., cyclosporin A), CTLA4-Ig, LEA-29Y,antibodies such as anti-ICAM-3, anti-IL-2 receptor (Anti-Tac),anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86,monoclonal antibody OKT3, agents blocking the interaction between CD40and gp39, such as antibodies specific for CD40 and/or gp39 (i.e.,CD154), fusion proteins constructed from CD40 and gp39 (CD40Ig andCD8gp39), inhibitors, such as nuclear translocation inhibitors, ofNF-kappa B function, such as deoxyspergualin (DSG), non-steroidalantiinflammatory drugs (NSAIDs) such as ibuprofen, steroids such asprednisone or dexamethasone, gold compounds, antiproliferative agentssuch as methotrexate, FK506 (tacrolimus, Prograf), mycophenolatemofetil, cytotoxic drugs such as azathiprine and cyclophosphamide,phosphodiesterase (PDE) inhibitors, antihistamines, p³⁸ MAPK inhibitors,LTD₄ inhibitors such as zafirlukast (ACCOLATE) and montelukast(SINGULAIR), TNF-α inhibitors such as tenidap, anti-TNF antibodies orsoluble TNF receptor such as etanercept (Enbrel), rapamycin (sirolimusor Rapamune), leflunimnide (Arava), and cyclooxygenase-2 (COX-2)inhibitors such as celecoxib (Celebrex) and rofecoxib (Vioxx), orderivatives thereof, and the PTK inhibitors disclosed in the followingU.S. patent applications, incorporated herein by reference in theirentirety: Ser. No. 60/056,770, filed Aug. 25, 1997 (Attorney Docket No.QA202*), Ser. No. 60/069,159, filed Dec. 9, 1997 (Attorney Docket No.QA202a*), Ser. No. 09/097,338, filed Jun. 15, 1998 (Attorney Docket No.QA202b), Ser. No. 60/056,797, filed Aug. 25, 1997 (Attorney Docket No.QA205*), Ser. No. 09/094,797, filed Jun. 15, 1998 (Attorney Docket No.QA205a), Ser. No. 60/065,042, filed Nov. 10, 1997 (Attorney Docket No.QA207*), Ser. No. 09/173,413, filed Oct. 15, 1998, (Attorney Docket No.QA207a), Ser. No. 60,076,789, filed Mar. 4, 1998 (Attorney Docket No.QA208*), and Ser. No. 09,262,525, filed Mar. 4, 1999 (Attorney DocketNo. QA208a). See the following documents and references cited therein:Hollenbaugh, D., Douthwright, J., McDonald, V., and Aruffo, A.,“Cleavable CD40Ig fusion proteins and the binding to sgp39”, J. Immunol.Methods (Netherlands), 188(1), p. 1-7 (Dec. 15, 1995); Hollenbaugh, D.,Grosmaire, L. S., Kullas, C. D., Chalupny, N. J., Braesch-Andersen, S.,Noelle, R. J., Stamenkovic, I., Ledbetter, J. A., and Aruffo, A., “Thehuman T cell antigen gp39, a member of the TNF gene family, is a ligandfor the CD40 receptor: expression of a soluble form of gp39 with B cellco-stimulatory activity”, EMBO J (England), 11(12), p 4313-4321(December 1992); and Moreland, L. W. et al., “Treatment of rheumatoidarthritis with a recombinant human tumor necrosis factor receptor(p75)-Fc fusion protein”, New England J. of Medicine, 337(3), p. 141-147(1997).

[0188] Exemplary classes of anti-cancer agents and cytotoxic agentsinclude, but are not limited to: alkylating agents, such as nitrogenmustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes;antimetabolites, such as folate antagonists, purine analogues, andpyrimidine analogues; antibiotics, such as anthracyclines, bleomycins,mitomycin, dactinomycin, and plicamycin; enzymes, such asL-asparaginase; farnesyl-protein transferase inhibitors; hormonalagents, such as glucocorticoids, estrogens/antiestrogens,androgens/antiandrogens, progestins, and luteinizing hormone-releasinghormone anatagonists, octreotide acetate; microtubule-disruptor agents,such as ecteinascidins or their analogs and derivatives;microtubule-stabilizing agents such as paclitaxel (Taxol®), docetaxel(Taxotere®), and epothilones A-F or their analogs or derivatives;plant-derived products, such as vinca alkaloids, epipodophyllotoxins,taxanes; and topoisomerase inhibitors; prenyl-protein transferaseinhibitors; and miscellaneous agents such as, hydroxyurea, procarbazine,mitotane, hexamethylmelamine, platinum coordination complexes such ascisplatin and carboplatin; and other agents used as anti-cancer andcytotoxic agents such as biological response modifiers, growth factors;immune modulators, and monoclonal antibodies. The compounds of theinvention may also be used in conjunction with radiation therapy.

[0189] Representative examples of these classes of anti-cancer andcytotoxic agents include, but are not limited to, mechlorethaminehydrochloride, cyclophosphamide, chlorambucil, melphalan, ifosfamide,busulfan, carmustin, lomustine, semustine, streptozocin, thiotepa,dacarbazine, methotrexate, thioguanine, mercaptopurine, fludarabine,pentastatin, cladribin, cytarabine, fluorouracil, doxorubicinhydrochloride, daunorubicin, idarubicin, bleomycin sulfate, mitomycin C,actinomycin D, safracins, saframycins, quinocarcins, discodermolides,vincristine, vinblastine, vinorelbine tartrate, etoposide, teniposide,paclitaxel, tamoxifen, estramustine, estramustine phosphate sodium,flutamide, buserelin, leuprolide, pteridines, diyneses, levamisole,aflacon, interferon, interleukins, aldesleukin, filgrastim,sargramostim, rituximab, BCG, tretinoin, irinotecan hydrochloride,betamethosone, gemcitabine hydrochloride, altretamine, and topoteca andany analogs or derivatives thereof.

[0190] Preferred members of these classes include, but are not limitedto paclitaxel, cisplatin, carboplatin, doxorubicin, carminomycin,daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C,ecteinascidin 743, porfiromycin, 5-fluorouracil, 6-mercaptopurine,gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxinderivatives such as etoposide, etoposide phosphate or teniposide,melphalan, vinblastine, vincristine, leurosidine, vindesine, andleurosine.

[0191] Examples of anti-cancer and other cytotoxic agents include thefollowing: epothilone derivatives as found in U.S. Ser. No. 09/506,481filed Feb. 17, 2000 (Attorney Docket No. LD186); German Patent No.4138042.8; WO 97/19086, WO 98/22461, WO 98/25929, WO 98/38192, WO99/01124, WO 99/02224, WO 99/02514, WO 99/03848, WO 99/07692, WO99/27890, WO 99/28324, WO 99/43653, WO 99/54330, WO 99/54318, WO99/54319, WO 99/65913, WO 99/67252, WO 99/67253, and WO 00/00485; cyclindependent kinase inhibitors as found in WO 99/24416; and prenyl-proteintransferase inhibitors as found in WO 97/30992 and WO 98/54966.

[0192] The above other therapeutic agents, when employed in combinationwith the compounds of the present invention, may be used, for example,in those amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

[0193] Compounds within the scope of the present invention can beassayed for Tec family tyrosine kinase inhibitory activity using methodssuch as those described by Hawkins, J. and Marcy, A. Prot. Express.Purif. 2001, 22, 211-219, employing modifications readily known to thoseof skill in the art.

[0194] The following example compounds are Tec family tyrosine kinaseinhibitors (especially Emt inhibitors) and illustrate embodiments of thepresent invention. These examples are not intended to limit the scope ofthe claims. Compounds of the Examples are identified by the example andstep in which they are prepared (for example, “1A” denotes the titlecompound of step A of Example 1), or by the example only where thecompound is the title compound of the example (for example, “2” denotesthe title compound of Example 2).

EXAMPLE 1N-[5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]phenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

[0195]

[0196] A. 3-[(2-Aminothiazol-5-yl)thio]benzoic Acid Methyl Ester

[0197] A 4.37 M solution of sodium methoxide in methanol (10 mL, 43.7mmol) was added dropwise to a stirred suspension of2-amino-5-bromothiazole hydrochloride (2.16 g, 10 mmol) and3-carboxythiophenol (1.85 g, 12 mmol) in methanol (75 mL) at 0-5° C. Thesolution was allowed to warm to rt. for 2 h and a 4 M solution ofhydrogen chloride in dioxane (15 mL, 60 mmol) was added. The suspensionwas stirred at rt. overnight and concentrated. The crude residue wasdiluted with satd. aqueous sodium bicarbonate solution (50 mL). Theprecipitated solid was filtered and washed with water (20 mL, 5×) andether (20 mL, 5×). The solid was filtered and dried in vacuo at 60° C.to obtain the titled compound (1.97 g, 75%).

[0198] B.3-[[2-[[(1,1-Dimethylethoxy)carbonyl]amino]thiazol-5-yl]thio]benzoicAcid Methyl Ester

[0199] Di-t-butylcarbonate (4.36 g, 20 mmol) was added to a stirredsolution of 2amino-5-[(3-carbomethoxyphenyl)thio]thiazole(1.33 g, 5mmol) and 4-N,N-dimethylaminopyridine (62 mg, 0.5 mmol) in THF (120 mL).The solution was stirred at rt. for 6 h and concentrated. The residuewas purified using flash column chromatography on silica gel. Elutionwith 10% EtOAc in hexanes followed by 25% EtOAc in hexanes afforded amixture of the titled compound and the correspondingbis(tert-butoxycarbonyl)amino adduct (1.8 g) as an oil.

[0200] C.3-[[2-[[(1,1-Dimethylethoxy)carbonyl]amino]thiazol-5-yl]thio]benzoicAcid

[0201] A 1 N aqueous sodium hydroxide solution (50 mL, 50 mmol) wasadded dropwise to a stirred solution of2-tert-butoxycarbonylamino-5-[(3-carbomethoxyphenyl)thio]thiazole (1.8g, (contaminated with bis(tert-butoxycarbonyl)amino adduct)) in amethanol-THF mixture (160 mL, 3: 1). The solution was stirred at rt. for24 h and concentrated. The residue was acidified with 2 N aqueous HCl(30 mL) and the suspension was extracted with dichloromethane-methanolmixture (120 mL, 3:1, 2×). The combined organic extract was dried(MgSO₄), filtered and concentrated in vacuo to obtain the titledcompound (1.32 g, 75% overall yield from Example 1, part A) as anoff-white solid.

[0202] D.5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]phenyl]thio]thiazol-2-ylcarbamicAcid 1,1-(dimethylethyl) Ester

[0203] A suspension of2-tert-butoxycarbonylamino-5-[(3-carboxyphenyl)thio]thiazole (528 mg,1.5 mmol), N-acetylpiperazine (239 mg, 1.87 mmol),ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (400 mg, 2mmol), 1-hydroxy-7-azabenzotriazole (272 mg, 2 mmol) anddiisopropylethylamine (560 μL, 4 mmol) in THF (20 mL) was heated to 55°C. for 2 h. The mixture was cooled to rt. and concentrated. The residuewas purified using column chromatography on silica gel eluted with 2%methanol in dichloromethane followed by 5% methanol in dichloromethaneto obtain the titled compound (400 mg, 58%) as a white foam.

[0204] E. 4-Acetyl-1-[3-[(2-aminothiazol-5-yl)thio]benzoyl]piperazine

[0205] A solution of2-tert-butoxycarbonylamino-5-[(3-N-acetylpiperazinylcarboxamidophenyl)thio]thiazole(400 mg, 0.87 mmol) in trifluoroacetic acid (6 mL) was stirred at rt.for 2 h. The solution was concentrated and the residue was partitionedbetween dichloromethane (30 mL) and satd. aqueous sodium bicarbonatesolution (20 mL). The aq. layer was extracted with dichloromethane (20mL). The dichloromethane extracts were combined, dried (MgSO₄), filteredand concentrated under reduced pressure and in vacuo to obtain thetitled compound (300 mg, 95%) as a white solid.

[0206] F.N-[5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]phenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

[0207] A stirred suspension of2-amino-5-[(3-N-acetylpiperazinylcarboxamido-phenyl)-thio]thiazole (30mg, 0.08 mmol), and 4-N,N-dimethylaminobenzoyl chloride (45.6 mg, 0.25mmol) in dichloromethane (6 mL) was cooled to 0° C. and treated withpyridine (130 μL). The cooling bath was removed and the solution wasstirred at rt. for 2 h. The mixture was concentrated in vacuo and theresidue was purified using reversed phase automated preparative HPLC(conditions: YMC S5 ODS A 20×100 mm column, 15 min gradient startingfrom 10% solvent B (90% MeOH, 10% H₂O, 0.1% TFA) and 90% solvent A (10%MeOH, 90% H₂0, 0.1% TFA) to 90% solvent B and 10% solvent A, flow rate20 mL/min, λ=220 nM to obtain the titled compound (8.7 mg, 21%) as ayellow solid: (M+H)⁺=510.27.

EXAMPLE 24-Acetyl-1-[5-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]thio]-2methylbenzoyl]piperazine

[0208]

[0209] A. N-[[N-(6-Bromopyridin-2-yl)amino]thioxo]benzamide

[0210] A solution of 2-amino-6-bromopyridine (3 g, 17.34 mmol) andbenzoyl isothiocyanate (2.3 mL, 17.34 mmol) in acetone (30 mL) wasstirred at rt. for 35 min. The suspension was cooled in an ice-waterbath, diluted with water (150 mL) and stirred for several min. Theprecipitate was filtered, washed with water and dried in vacuo. Thesolid was triturated with ether to obtain the titled compound (4.99 g,86%) as an off-white solid.

[0211] B. N-(6-Bromopyridin-2-yl)thiourea

[0212] A suspension of 2-bromo-6-benzoylthioureidopyridine (4.99 g,14.84 mmol) in 10% aqueous sodium hydroxide solution (10.4 mL, 26 mmol)was stirred at rt. for 10 min and then under reflux for an additional 10min. The mixture was cooled to 0° C. and acidified with 1 N aqueous HClsolution to pH 4.0 and then adjusted to pH 8.5 with satd. aqueouspotassium bicarbonate solution. The mixture was stirred at 0° C. forseveral min and the precipitate was filtered, washed several times withwater and dried in vacuo over P₂O₅ to obtain the titled compound (3.23g, 94%) as a white solid.

[0213] C. 6-Bromo-N-(2-thiazolyl)pyridin-2-amine

[0214] A suspension of 2-bromo-6-thioureidopyridine (3 g, 12.92 mmol)and chloroacetaldehyde (3.28 mL, 25.85 mmol) in ethanol (27 mL) andwater (7 mL) was heated at reflux for 4.75 h. The solution wasconcentrated in vacuo and the residue was diluted with 1 N aqueous NaOHsolution at 0° C., stirred for 10 min, and the pH was then adjusted to8.5 by addition of 6 N aqueous HCl solution. The precipitate wascollected by filtration, washed several times with water and dried invacuo over P₂O₅ to obtain the titled compound (3.17 g, 96%) as a lightyellow solid.

[0215] D. 6-Bromo-N-(5-bromo-2-thiazolyl)pyridin-2-amine

[0216] A solution of bromine (1.1 mL, 20.9 mmol) in acetic acid (15 mL)was added dropwise to a solution of2-[(6-bromo-2-pyridinyl)amino]thiazole (2.68 g, 10.46 mmol) in aceticacid (23 mL) at 40° C. After addition, the mixture was stirred at rt.for 3 h. The mixture was diluted with aqueous potassium hydrogen sulfatesolution (60 mL) at 0° C. and stirred for several min. The precipitatedsolid was filtered, washed several times with water and dried in vacuoover P₂O₅ to obtain the titled compound (3.28 g, 94%) as an off-whitesolid.

[0217] E.5-[[2-[N-(6-Bromopyridin-2-yl)amino]thiazol-5-yl]thio]-2-methylbenzoicAcid

[0218] A suspension of 2-[(6-bromo-2-pyridinyl)amino]-5-bromothiazole(100 mg, 0.3 mmol), 3-carboxy-4-methylthiophenol (170 mg, 0.98 mmol) andsodium methoxide (210 μL, 25% w/w solution in methanol, 0.9 mmol) inmethanol (4.9 mL) and THF (2 mL) was heated to 54° C. for 5.5 h.Supplemental sodium methoxide solution (1.42 mL) was added in portionsover a period of 5 h. The mixture was heated to 54° C. for 16 h andconcentrated. The residue was diluted with 1 N aqueous HCl solution at0° C. and stirred for several minutes. The precipitated solid wasfiltered, washed several times with water and ether, and dried in vacuoover P₂O₅. Trituration with ether afforded the titled compound (103 mg,81%) as an off-white solid.

[0219] F.4-Acetyl-1-[5-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]thio]-2methylbenzoyl]piperazine

[0220] A suspension of2-[(6-bromo-2-pyridinyl)amino]-5-(3-carboxy-4methylphenyl-1-thio)thiazole(103 mg, 0.24 mmol), N-acetylpiperazine (37.2 mg, 0.29 mmol),ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (55.6 mg,0.29 mmol), 1-hydroxy-7-azabenzotriazole (39.5 mg, 0.29 mmol) anddiisopropylethylamine (130 μL, 0.72 mmol) in THF (10.5 mL) was heated to58° C. for 1 h. The mixture was concentrated in vacuo and the residuewas purified using column chromatography on silica gel. Elution with 1%methanol in dichloromethane followed by 2% and 4% methanol indichloromethane afforded the titled compound (110 mg, 86%) as a yellowsolid: mass spectrum (M+H)⁺=533.89.

EXAMPLE 34-Acetyl-1-[5-[[2-[N-(2-pyridinyl)amino]thiazol-5-yl]thio]-2-methylbenzoyl]piperazine

[0221]

[0222] A. N-[[N-(2-Pyridinyl)amino]thioxo]benzamide

[0223] This material was prepared by an analogous method as that ofExample 2, part A, except using 2-aminopyridine to give the titlecompound as an ochre solid (100%).

[0224] B. N-(2-Pyridinyl)thiourea

[0225] This material was prepared by an analogous method as thatdescribed in Example 2, part B, except using the compound described inExample 3, part A to give the title compound as a yellow powder (73%).

[0226] C. N-(2-Thiazolyl)-2-pyridinamine

[0227] Example 3C was prepared by an analogous method as that of Example2C, except using the compound described in Example 3, part B to give thetitle compound as an off-white solid (79%).

[0228] D. N-(5-Bromothiazol-2-yl)-2-pyridinamine

[0229] Example 3D was prepared by an analogous method as that of Example2D, except using the compound described in Example 3, part C to give thetitle compound as an off-white solid (95%).

[0230] E. 2-Methyl-5-[[2-[N-(2-pyridinyl)amino]thiazol-5-yl]thio]benzoicAcid

[0231] Example 3E was prepared by an analogous method as that of Example2E, except using the compound described in Example 3, part D to give thetitle compound as a pale tan solid (84%).

[0232] F.4-Acetyl-1-[5-[[2-[N-(2-pyridinyl)amino]thiazol-5-yl]thio]-2methylbenzoyl]piperazine

[0233] Example 3F was prepared by an analogous method as that of Example2F, except using the compound described in Example 3, part E to give thetitle compound as an off-white solid: mass spectrum (M+H)⁺=454.11.

EXAMPLE 44-Acetyl-1-[3-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]thio]benzoyl]piperazine

[0234]

[0235] A. 3-[[2-[N-(6-Bromopyridin-2-yl)amino]thiazol-5-yl]thio]benzoicAcid

[0236] Example 4A was prepared by an analogous method as that of Example2E, except using 3-carboxythiophenol in place of3-carboxy-4-methylthiophenol to give the title compound as a solid.

[0237] B.4-Acetyl-1-[3-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]thio]benzoyl]piperazine

[0238] Example 4B was prepared by an analogous method as that of Example2F, except using the compound described in Example 4, part A to give thetitle compound as a light peach-colored solid: mass spectrum(M+H)⁺=520.13.

EXAMPLE 54-Acetyl-1-[3-[[2-[N-(2-pyridinyl)amino]thiazol-5-yl]thio]benzoyl]piperazine

[0239]

[0240] A. 3-[[2-[N-(2-Pyridinyl)amino]thiazol-5-yl]thio]benzoic Acid

[0241] Example 5A was prepared by an analogous method as that of Example2E, except using the compound described in Example 3, part D and3-carboxythiophenol in place of 3-carboxy-4-methylthiophenol to give thetitle compound as a solid.

[0242] B.4-Acetyl-1-[3-[[2-[N-(2-pyridinyl)amino]thiazol-5-yl]thio]benzo-yl]piperazine

[0243] Example 5B was prepared by an analogous method as that of Example2F, except using the compound described in Example 5, part A to give thetitle compound as an off-white solid: mass spectrum (M+H)⁺=440.3.

EXAMPLE 64-Acetyl-1-[3-[[2-[N-(6-methylpyridin-2-yl)amino]thiazol-5-yl]thio]benzoyl]piperazine

[0244]

[0245] Example 6 was prepared by an analogous method as that of Example2, except using 2-amino-6-methylpyridine in place of2-amino-6-bromopyridine in Example 2A and 3-carboxythiophenol in placeof 3-carboxy-4-methylthiophenol in Example 2E to give the title compoundas a white solid: mass spectrum (M+H)⁺=454.11.

EXAMPLE 74-Acetyl-1-[3-[[2-[N-(5-bromo-6-methylpyridin-2-yl)amino]thiazol-5-yl]thio]benzoyl]piperazine

[0246]

[0247] Example 7 was prepared by an analogous method as that of Example2, except using 2-amino-5-bromo-6-methylpyridine in place of2-amino-6bromopyridine in Example 2A and 3-carboxythiophenol in place of3-carboxy-4-methylthiophenol in Example 2E to give the title compound asa light tan solid: mass spectrum (M+H)⁺=534.

EXAMPLE 84-Acetyl-1-[3-[[2-[N-(2-quinolinyl)amino]thiazol-5-yl]thio]benzoyl]piperazine

[0248]

[0249] Example 8 was prepared by an analogous method as that of Example2, except using 2-amino-quinoline in place of 2-amino-6-bromopyridine inExample 2A and 3-carboxythiophenol in place of3-carboxy-4-methylthiophenol in Example 2E to give the title compound asa yellow solid: mass spectrum (M+H)⁺=490.08.

EXAMPLE 94-Acetyl-1-[3-[[2-[N-(2-pyridinyl)amino]thiazol-5-yl]thio]-4-methylbenzoyl]piperazine

[0250]

[0251] Example 9 was prepared by an analogous method as that of Example2, except using 2-amino-pyridine in place of 2-amino-6-bromopyridine inExample 2A and 3-carboxy-6-methylthiophenol in place of3-carboxy-4-methylthiophenol in Example 2E to give the title compound asa white solid: mass spectrum (M+H⁺=454.13.

EXAMPLE 104-Acetyl-1-[3-[[2-[N-[6-(1-piperidinyl)pyridin-2-yl]amino]thiazol-5-yl]thio]benzoyl]piperazine

[0252]

[0253] A solution of Example 4 (30 mg, 0.058 mmol), piperidine (86 μL,0.87 mmol), 4-dimethylaminopyridine (7.1 mg, 0.058 mmol) in pyridine(300 μL) was heated to 134° C. in a sealed vial under nitrogen for 8.75h. Most of pyridine was removed on a speed-vac at 40° C. The residue waspurified using reversed phase automated preparative HPLC (conditions:YMC S5 ODS A 20×100 mm column, 15 min gradient starting from 10% solventB (90% MeOH, 10% H₂O, 0.1% TFA) and 90% solvent A (10% MeOH, 90% H₂O,0.1% TFA) to 90% solvent B and 10% solvent A, flow rate 20 mL/min, λ=220nM) to obtain the titled compound (25.2 mg, 68%) as a light tan solid.

EXAMPLES 11 THROUGH 22

[0254] General Procedure

[0255] Polymer-supported diisopropylethylamine (37.6 mg, 0.124 mmol) wasdispensed into each well of a 48 well Mini-block reactor. A 0.087 Msolution of the appropriate amines in THF-DMF mixture (1 mL, 9:1) wasadded to each well using the TECAN liquid handler. A solution of thecarboxylic acid described in procedure 3E (10 mg, 0.029 mmol),ethyl-3-(3-dimethylamino)propylcarbodiimide hydrochloride (6.71 mg,0.035 mmol), 1-hydroxy-7-azabenzotriazole (4.76 mg, 0.035 mmol) inTHF-DMF mixture (1 mL, 4:1) was added to each well using the TECANliquid handler. The Mini-block was sealed and mechanically shaken at 60°C. for 5 h and at room temperature for an additional 16 h. Polystyrenesupported methylisocyanate resin (109.5 mg, Novabiochem) was added toeach well and shaking was continued at room temperature for 16 h. Eachreaction mixture was loaded onto cation-exchange cartridges (CUBCX1HL,size: 500 mg/3 mL, United Chemical Technologies) and eluted sequentiallywith THF (8 mL), MeOH (8 mL), and 0.2 N ammonia in MeOH (4 mL).Fractions containing products were concentrated using a speed-vac.Residues were dissolved in THF-DMF mixture (9:1) and passed throughanion exchange cartridges (CHQAX1, size: 500 mg/3 mL, United ChemicalTechnologies) and eluted with MeOH (2 mL). Fractions containing theproducts were concentrated using the speed-vac to give Examples 11-22.Ex. MS No. Name Structure (M + H)⁺ 11 4-(2-Pyrimidinyl)-1-[5-[[2- [N-(2-pyridinyl)amino]thiazol- 5-yl]thio]-2- methylbenzoyl]piperazine

488.3 12 4-Hydroxy-1-[5-[[N-(2- pyridinyl)amino]thiazol- 5-yl]thio]-2-methylbenzoyl]piperidine

427.33 13 1,2,5,6-Tetrahydro-1-[5 [[2-[N-(2- pyridinyl)amino]thiazol-5-yl]thio]-2- methylbenzoyl]pyridine

409.2 14 4-[2-(4-Morpholinyl)-2-nl oxoethyl]-1-[5-[[2-[N-(2-pyridinyl)amino]thiazol- 5-yl]thio]-2- methylbenzoyl]piperazine

456.2 15 3-(Hydroxymethyl)-1-[5- [[2-[N-(2- pyridinyl)amino]thiazol-5-yl]thio]-2- methylbenzoyl]piperidine

441.15 16 4-(1-Piperidinyl)-1-[5-[[2- [N-(2- pyridinyl)amino]thiazol-5-yl]thio]-2- methylbenzoyl]piperidine

494.3 17 4-Formyl-1-[5-[[2-[N-(2- pyridinyl)amino]thiazol- 5-yl]thio]-2-methylbenzoyl]piperazine

440.08 18 3-Methyl-1-[5-[[2-[N-(2- pyridinyl)amino]thiazol-5-yl]thio]-2- methylbenzoyl]piperidine

425.18 19 N-Methyl-N-phenyl-4-[5- [[2-[N-(2- pyridinyl)amino]thiazol-5-yl]thio]-2- methylbenzoyl]-1- piperazineacetamide

559.3 20 4-[5-[[2-[N-(2- Pyridinyl)amino]thiazol- 5-yl]thio]-2-methylbenzoyl]-1- piperazineacetic acid ethyl ester

498.18 21 N-(2-Cyanoethyl)-2- methyl-5-[[2-[N-(2-pyridinyl)amino]thiazol- 5-yl]thio]benzamide

396.14 22 N-Cyanomethyl)-2- methyl-5-[[2-[N-(2- pyridinyl)amino]thiazol-5-yl]thio]benzamide

382.12

EXAMPLE 23N-[5-[[5-[(4-Acetylpiperazin-1-yl)carbonyl]-2-methylphenyl]thio]thiazol-2yl]-4-(N,N-dimethylamino)benzamide

[0256]

[0257] A. 3-[(2-Aminothiazol-5-yl)thio]-4-methylbenzoic Acid MethylEster

[0258] A 4.37 M solution of sodium methoxide in methanol (4.75 mL, 20.76mmol) was added dropwise to a stirred suspension of2-amino-5-bromothiazole hydrobromide (1.25 g, 4.8 mmol) and3-carboxy-6-methyl-thiophenol (0.74 g, 4.4 mmol) in methanol (75 mL) at0-5° C. The solution was stirred at 75° C. overnight.

[0259] The mixture was concentrated in vacuo and the residue wasdissolved in water and then acidified with aqueous HCl solution. Theprecipitated brown solid was filtered, washed with water and dried invacuo to obtain the carboxylic acid (1.15 g). A solution of this acid inMeOH, 4 N hydrogen chloride in dioxane and conc. H₂SO₄ (20 drops) washeated under reflux for 3 days. The solution was concentrated and theresidue was partitioned between EtOAc and satd. aqueous NaHCO₃ solution.The EtOAc extract was washed with satd. aqueous NaHCO₃ solution, dried(Na₂SO₄), filtered and concentrated in vacuo to obtain the titlecompound (1 g, 81%) as a yellowish-brown solid.

[0260] B.3-[[2-[[4-(N,N-Dimethylamino)benzoyl]amino]thiazol-5-yl]thio]-4methylbenzoicAcid Methyl Ester

[0261] A suspension of compound A (1 g, 3.6 mmol), and4-N,N-dimethylaminobenzoyl chloride (1.31 g, 7.1 mmol) indichloromethane (25 mL) and pyridine (1 mL) was stirred at rt. for 2days. Supplemental 4-N,N-dimethylaminobenzoyl chloride (500 mg, 2.72mmol) was added and the mixture was stirred at rt. overnight. Thesolution was partitioned between dichloromethane and water. Thedichloromethane extract was washed with 1 N aq. HCl solution, satd. aq.NaHCO₃ solution, dried (Na₂SO₄), filtered, and concentrated in vacuo toobtain the crude product, which was used without further purification.

[0262] C.3-[[2-[[4-(N,N-Dimethylamino)benzoyl]amino]thiazol-5-yl]thio]-4-methylbenzoicAcid

[0263] A 1 N aqueous sodium hydroxide solution (25 mL, 25 mmol) wasadded dropwise to a stirred solution of crude compound B in methanol.The solution was stirred at rt. for 72 h and concentrated. The residuewas partitioned between dichloromethane and water. The aqueous extractwas acidified with 1 N aqueous HCl solution and the precipitated solidwas collected by filtration and dried in vacuo to obtain the titlecompound C (850 mg, 58%) as a tan solid.

[0264] D.N-[5-[[5-[(4-Acetylpiperazin-1-yl)carbonyl]-2-methylphenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

[0265] A suspension of compound C (380 mg, 0.92 mmol),N-acetylpiperazine (236 mg, 1.84 mmol), ethyl-3-(3-dimethylamino)propylcarbodiimide hydrochloride (350 mg, 1.8 mmol),1-hydroxy-7-azabenzotriazole (250 mg, 1.8 mmol) anddiisopropylethylamine (1 mL, 7.1 mmol) in THF (20 mL) was heated to 66°C. overnight. The mixture was cooled to rt. and concentrated. Theresidue was purified using reversed phase automated preparative HPLC(conditions: YMC S5 ODS A 20×100 mm column, 15 min gradient startingfrom 10% solvent B (90% MeOH, 10% H₂O, 0.1% TFA) and 90% solvent A (10%MeOH, 90% H₂O, 0.1% TFA ) to 90% solvent B and 10% solvent A, flow rate20 mL/min, λ=220 nM) to obtain the title compound (73 mg, 15% yield) asa yellow solid: mass spectrum (M +H)⁺=524.14.

EXAMPLE 24N-[5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4-methylphenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

[0266]

[0267] Compound 24 was prepared by an analogous method as that of 23,except substituting 3-carboxy-4-methylthiophenol in place of3-carboxy-6-methylthiophenol in Example 23A to give the title compound24 as an orange solid: mass spectrum (M+H)⁺=524.11.

EXAMPLE 25N-[5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4,5-dimethylphenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

[0268]

[0269] Example 25 was prepared by an analogous method as that of Example23, except substituting 3-carboxy-4,5-dimethylthiophenol for3-carboxy-6-methylthiophenol in Example 23A to give the title compoundas a light salmon colored solid: mass spectrum (M+H)⁺=538.33.

Example 26N-[5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4-aminophenyl]thio]thiazol-2yl]-4-(N,N-dimethylamino)benzamide

[0270]

[0271] Example 26 was prepared by an analogous method as that of 23,except substituting 3-carboxy-4-acetamido-thiophenol for3-carboxy-6-methylthiophenol in Example 23A to give the title compoundas a yellow solid: mass spectrum (M+H)⁺=525.21.

EXAMPLE 27N-[5-[[5-[(4-Acetylpiperazin-1-yl)carbonyl]-2,4-dimethylphenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

[0272]

[0273] Example 27 was prepared by an analogous method as that of 23,except substituting 3-carboxy-4,6-dimethylthiophenol for3-carboxy-6-methylthiophenol in Example 23A to give the title compoundas a light amber solid: mass spectrum (M+H)⁺=538.44.

EXAMPLE 28N-[5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4-hydroxyphenyl]thio]thiazol-2-yl]-4-(N,N-dimethylamino)benzamide

[0274]

[0275] Example 28 was prepared by an analogous method as that of 23,except substituting 3-carboxy-4-hydroxy-thiophenol for3-carboxy-6-methylthiophenol in Example 23A to give the title compoundas a yellow solid: mass spectrum (M+H)⁺=526.45.

EXAMPLE 29N-[5-[[5-[(4-Acetylpiperazin-1-yl)carbonyl]-2,4-dimethylphenyl]thio]thiazol-2-yl]-4-(1,1-dimethylethyl)benzamide

[0276]

[0277] Example 29 was prepared by an analogous method as that of 23,except substituting 3-carboxy-4,6-dimethylthiophenol for3-carboxy-6-methylthiophenol in Example 23A and substituting4-tert-butylbenzoyl chloride for 4-N,N-dimethylaminobenzoyl chloride inExample 23B to give the title compound as an amber solid: mass spectrum(M+H)⁺=551.12.

EXAMPLE 304-(1,1-Dimethylethyl)-N-[5-[[5-[(4-hydroxypiperidin-1-yl)carbonyl]-2,4-dimethylphenyl]thio]thiazol-2-yl]benzamide

[0278]

[0279] Example 30 was prepared by an analogous method as that of 23,except substituting 3-carboxy-4,6-dimethylthiophenol for3-carboxy-6-methylthiophenol in Example 23A, substituting4-t-butylbenzoyl chloride for 4-N,N-dimethylaminobenzoyl chloride inExample 23B and substituting 4-hydroxypiperidine for N-acetylpiperazinein Example 23D to give the title compound as an amber solid: massspectrum (M+H)⁺=524.32.

EXAMPLE 31N-[5-[[[3-[(4-Acetylpiperazin-1-yl)carbonyl]phenyl]methoxy]methyl]thiazol-2-yl]-4-(1,1dimethylethyl)benzamide

[0280]

[0281] A. 2-[N-[4-(1,1-Dimethylethyl)benzoyl]amino]thiazole-5-carboxylicAcid Ethyl Ester

[0282] A solution of ethyl 2-aminothiazole-5-carboxylate (0.52 g, 3.0mmol), 4-t-butylbenzoyl chloride (1.3 mL, 6.7 mmol) and pyridine (1.2mL) in dichloromethane (10 mL) was stirred at 0° C. for 1.25 h. It wasthen diluted with dichloromethane and washed with aqueous HCl (1 N)twice, saturated aqueous sodium bicarbonate, and brine. After dryingover sodium sulfate, filtration and concentration in vacuo gave aburgundy oil. Trituration with hexane afforded the desired amide as alight tan solid (0.88 g, 88% yield): LC/MS RT=3.85 min; mass spectrum(M+H)⁺=333.16.

[0283] B.4-(1,1-Dimethylethyl)-N-[(5-hydroxymethyl)thiazol-2-yl]benzamide

[0284] To a light tan suspension of ethyl2-[[4-(1,1-dimethylethyl)phenyl)carbonyl]amino]-thiazole-5-carboxylate(0.88 g, 2.6 mmol) in tetrahydrofuran (7.0 mL) under nitrogen at 0° C.was added dropwise lithium aluminum hydride (1 M in THF, 10.6 mL). After1.75 h, ice was added, followed by 1 N aqueous HCl. The mixture wasextracted using ethyl acetate, and the combined organic layers weredried over sodium sulfate, filtered, and concentrated in vacuo to givethe desired product as a light yellow solid (0.73 g, 95% yield): LC/MSRT=3.11 min; mass spectrum (M+H)⁺=291.13.

[0285] C. 4-Acetyl-1-(3-chloromethyl)benzoylpiperazine

[0286] To a solution of 3-chloromethylbenzoyl chloride (5.34 g, 28.2mmol) in dichloromethane (25 mL) was added a solution of1-acetylpiperazine (7.30 g, 57.0 mmol) in dichloromethane (25 mL) at 0°C. over 10 min. The resulting mixture was stirred at 0° C. for 1 hourand then at room temperature for another hour. During the reactionperiod, the mixture became cloudy. It was diluted with dichloromethane,washed with water, 1 N HCl, water, brine, and dried over anhydrousMgSO₄. Evaporation of solvent gave the desired product (7.92 g, 100%) asa pale yellow viscous oil: LC/MS RT=0.92 min; mass spectrum(M+H)⁺=281.19.

[0287] D.N-[5-[[[3-[(4-Acetylpiperazin-1-yl)carbonyl]phenyl]methoxylmethyl]thia-zol-2-yl]-4-(1,1-dimethylethyl)benzamide

[0288] To a solution of2-[[4-(1,1-dimethylethyl)phenyl)carbonyl]amino]-5-hydroxymethylthiazole(0.285 g, 0.983 mmol) and N-acetylpiperazinyl-(3-chloromethyl)benzamide(0.276 g, 0.983 mmol) in DMF (30 mL) at 0° C. was added NaH (60%dispersion in mineral oil, 0.197 g, 4.92 mmol). The mixture was heatedat 60° C. overnight and was quenched by adding MeOH. The solution wasneutralized to pH 8 using 1 N HCl and diluted with ethyl acetate Thesolution was then washed with water, brine, dried over anhydrous MgSO₄,and concentrated under vacuum. The residue was purified using flashcolumn chromatography (5% MeOH/CHCl₃) to afford 30 mg of the desiredmaterial as a white solid: LC/MS RT=3.49 min; mass spectrum(M+H)⁺=535.20.

EXAMPLE 324-(1,1-Dimethylethyl)-N-[5-[[[3-[[4-(2-pyrimidinyl)piperazin-1-yl]-carbonyl]-4-methylphenyl]thio]methyl]thiazol-2-yl]benzamide

[0289]

[0290] A.N-[(5-Chloromethyl)thiazol-2-yl]-4-(1,1-dimethylethyl)benzamide

[0291] To a solution of2-[[4-(1,1-dimethylethyl)phenyl)carbonyl]amino]-5hydroxymethylthiazole(1.50 g, 5.16 mmol) in dichloromethane (40 mL) was added thionylchloride (1.50 mL, 20.6 mmol) at 0° C. The mixture was stirred for 2 h,after which the reaction was complete, as indicated by HPLC. Evaporationof solvent and excess thionyl chloride provided the desired material(1.58 g, 99%) as a pale yellow solid.

[0292] B.5-[[[2-[[4-(1,1-Dimethylethyl)benzoyl]amino]thiazol-5-yl]methyl]thiol]-2-methylbenzoicAcid

[0293] To a solution of 3-mercapto-2-methylbenzoic acid (0.270 g, 1.60mmol) in DMF (5 mL) was added KOBu^(t) (0.378 g, 3.20 mmol) at 0° C. Themixture was stirred at 0° C. for 20 min before5-chloromethyl-2-[[4-(1,1-dimethylethyl)phenyl)carbonyl]-amino]thiazole(0.445 g, 1.44 mmol) was added. The mixture was stirred at 0° C. for 1 hand then poured into water (20 mL). The solution was acidified to pH 2using 1 N HCl. The precipitate was collected by filtration and driedover drierite under vacuum. The product (0.489 g, 77%) was obtained as awhite solid: LC/MS RT=3.96 min; mass spectrum (M+H)⁺=441.14.

[0294] C.4-(1,1-Dimethylethyl)-N-[5-[[[3-[[4-(2-pyrimidinyl)piperazin-1-yl]carbonyl]-4-methylphenyl]thio]methyl]thiazol-2-yl]benzamide

[0295] A mixture of the product of Example 32, part B (0.250 g, 0.567mmol), 1-(2-pyrimidyl)piperazine (0.121 g, 0.737 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate(0.476 g, 1.08 mmol), 4-methylmorpholine (0.31 mL, 2.82 mmol) in DMF (6mL) was heated at 65° C. for 5 h. The mixture was then diluted withethyl acetate, washed with water, 1N NaOH solution, water, and brine.The solution was dried over anhydrous MgSO₄ and concentrated undervacuum. The residue was purified using flash column chromatography(ethyl acetate) to provide the desired product (0.210 g, 63%) as a whitesolid: LC/MS RT=3.94 min; mass spectrum (M+H)⁺=587.42.

EXAMPLE 33N-[5-[[N-[3-[(4-Acetylpiperazin-1-yl)carbonyl]phenylmethyl]-N-methylamino]methyl]thiazol-2-yl]-4-(1,1-dimethylethyl)benzamide

[0296]

[0297] A. 4-Acetyl-1-[3-[(N-methylamino)methyl]benzoyl]piperazine

[0298] To N-Acetylpiperazinyl-(3-chloromethyl)benzamide (32C, 0.884 g,3.15 mmol) was added methylamine (2.0 M in MeOH, 4.7 mL). The mixturewas stirred at room temperature overnight. It was then diluted withwater (20 mL), adjusted to pH 11 using 10% NaCO₃ solution, and extractedwith ethyl acetate (5×30 mL). The combined organic extract was driedover anhydrous MgSO₄ and concentrated under vacuum. The residue waspurified using flash column chromatography (30% MeOH/CHCl₃-80%MeOH/CHCl₃) to afford the desired amine (0.142 g, 16%) as a pale yellowviscous oil; LC/MS RT=1.42 min, mass spectrum (M+H)⁺=276.23.

[0299] B.N-[5-[[N-[3-[(4-Acetylpiperazin-1-yl)carbonyl]phenylmethyl]-N-methylamino]methyl]thiazol-2-yl]-4-(1,1-dimethylethyl)benzamide

[0300] To a solution of 33A (72.0 mg, 0.261 mmol) in THF (3 mL) wasadded5-chloromethyl-2-[[4-(1,1-dimethylethyl)phenyl)carbonyl]amino]thiazole(32A, 80.0 mg, 0.259 mmol) in one portion at 0° C. The mixture wasstirred room temperature for 3 h and then at 45° C. for 2 h. It was thendiluted with water (20 mL), adjusted to pH 11 using 10% NaCO₃ solution,and extracted with ethyl acetate (5×30 mL). The combined extract wasdried over anhydrous MgSO₄ and concentrated in vacuo. The residue waspurified using preparative HPLC to afford 13.3 mg of the desiredmaterial as a TFA salt; LC/MS RT=2.60 min, mass spectrum (M+H)⁺=548.28.

EXAMPLE 34N-[5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4-methyl-6-methoxy-phenyl]thio]thiazol-2-yl]-4-(N-1,2-dimethylpropylaminomethyl)benzamide

[0301]

[0302] A. [3-[(2-Aminothiazol-5-yl)thio]-4-methyl-6-methoxy]benzoic Acid

[0303] A 4.37 M solution of sodium methoxide in methanol (33.7 mL, 147.3mmol) was added dropwise to a stirred suspension of2-amino-5-bromothiazole hydrobromide (9.96 g, 38.3 mmol) and3-carboxy-4-methoxy-6-methyl-thiophenol (5.84 g, 27.5 mmol) in methanol(95 mL) at 0-5° C. under argon. The cooing bath was removed and thesolution was stirred at rt. for 1 hr. The mixture was cooled to 0° C.and acidified with a 4 M solution of hydrogen chloride in dioxane (37mL, 148 mmol). Supplemental hydrogen chloride in dioxane was addedslowly to adjust the pH to 2. Precipitated salts were filtered andwashed with methanol. The filtrate was concentrated under reducedpressure and the residual solid was washed with water (2×15 mL). Thesolid was dried in vacuo, and triturated with ether to obtain the titledcompound (8.52 g, 87%) as a tan solid.

[0304] B.5-[[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4-methyl-6-methoxy]phenyl]thio]-2-amino-thiazole

[0305] A suspension of[3-[(2-aminothiazol-5-yl)thio]-4-methyl-6methoxy]benzoic acid (2 g, 6mmol), N-acetylpiperazine (3.1 g, 24 mmol),ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (2.3 g, 12mmol), 1-hydroxy-7-azabenzotriazole (980 mg, 7.2 mmol) anddiisopropylethylamine (4.2 mL, 24 mmol) in THF (50 mL) and DMF (6 mL)was heated to 64° C. for 2.25 hr. The mixture was cooled to rt. andconcentrated in vacuo. The residue was dissolved in dichloromethane andwashed with water (50 mL) and 1 N aq. HCl solution (4×100 mL). Theaqeous layers were combined, brought to slightly alkaline pH using 1 Naq. NaOH solution and extracted with dichloromethane (6×70 mL). Thedichloromethane extracts were combined, dried (Na₂SO₄), filtered, andconcentrated. The residue was triturated with ether (90 mL) to obtainthe titled product (1.99 g, 82%) as a light tan solid.

[0306] C.N-[5-[[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4-methoxy-6-methyl]phenyl]thio]thiazol-2-yl]-4-(chloromethyl)benzamide

[0307] A solution of5-[[[3-[(4-acetylpiperazin-1-yl)carbonyl]-4-methyl-6-methoxy]phenyl]thio]-2-aminothiazole(102 mg, 0.28 mmol), 4-chloromethyl-benzoyl chloride (53 mg, 0.28 mmol)and diisopropylethyl amine (140 μL, 1 mmol) in dichloromethane (8 mL)was stirred at rt. for 3 hr. Supplemental 4-chloromethylbenzoyl chloride(26 mg, 0.14 mmol) was added and the solution was stirred for anadditional 4 hr. The mixture was diluted with dichloromethane (40 mL)and washed with 1 N aq. HCl solution (2×10 mL) and aq. NaHCO₃ solution(2×15 mL). The dichloromethane extract was dried (MgSO₄), filtered, andconcentrated in vacuo to obtain the crude titled product (205 mg) as ayellow foam.

[0308] D.N-[5-[[3-[(4-Acetylpiperazin-1-yl)carbonyl]-4-methyl-6-methoxy-phenyl]thio]thiazol-2-yl]-4-(N-1,2-dimethylpropylaminomethyl)benzamide

[0309] A solution of crudeN-[5-[[[3-[(4-acetylpiperazin-1-yl)carbonyl]-4-methoxy-6-methyl]phenyl]thio]thiazol-2-yl]-4-(chloromethyl)benzamide(205 mg, 0.25 mmol) and 1,2-dimethylpropyl amine (87 mg, 1 mmol) inmethanol (10 mL) was heated to 60° C. in a sealed tube for 24 hr. Themixture was cooled to rt. and concentrated in vacuo. The residue waspurified using reverse phase automated preparative HPLC (conditions: YMCS5 ODS 30×250 mm column, 30 min gradient starting from solvent A (10%MeOH, 90% H₂O, 0.1% TFA) to solvent B (90% MeOH, 10% H₂O, 0.1% TFA),flow rate 25 mL/min, λ=220 nM) to obtain the titled compound as a TFAsalt (100 mg, 55% yield over two steps, white foam); LC/MS RT=2.79 min;mass spectrum (M+H)⁺=610.32.

EXAMPLE 354-Acetyl-1-[5-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]oxo]-2-methylbenzoyl]piperazine

[0310]

[0311] A.5-[[2-[N-(6-Bromopyridin-2-yl)amino]thiazol-5-yl]oxo]-2-methylbenzoicAcid Ethyl Ester

[0312] A suspension of 2-[(6-bromo-2-pyridinyl)amino]-5-bromothiazole(Example 2, part D: 400 mg, 1.19 mmol), ethyl 3-hydroxy-6-methylbenzoate(330 mg, 1.79 mmol) and cesium carbonate (1.6 g, 4.76 mmol) in acetone(16 mL) was heated under reflux for 16 hr. The mixture was cooled to rt.and cesium carbonate was filtered through a Whatman Autovial PTFEfilter. The filtrate was concentrated, diluted with dichloromethane andfiltered. The filtrate was concentrated and the residual brown oil waspurified using silica gel column chromatography. Elution with 5% EtOAcin hexanes followed by 10%, 20%, 30%, and 50% EtOAc in hexanes affordedthe title product (90 mg, 21%) as a light tan solid.

[0313] B.5-[[2-[N-(6-Bromopyridin-2-yl)amino]thiazol-5-yl]oxo]-2-methylbenzoicAcid

[0314] A solution of5-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]oxo]-2-methylbenzoicacid ethyl ester (90 mg, 0.21 mmol) and 1 N aq. NaOH solution (1.3 mL,1.3 mmol) in THF (2 mL) and ethanol (2 mL) was stirred at rt. for 24 hr.The mixture was cooled to 0° C. and acidified with 6 N aq. HCl solution.After eveporation of the solvents in vacuo, the residue was diluted withwater and the precipitate was filtered, washed with water, and dried invacuo to obtain the titled compound (57 mg, 67%) as a yellow solid.

[0315] C.4-Acetyl-1-[5-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]oxo]-2-methylbenzoyl]piperazine

[0316] A suspension of5-[[2-[N-(6-bromopyridin-2-yl)amino]thiazol-5-yl]oxo]-2methylbenzoicacid (27.9 mg, 0.07 mmol), N-acetylpiperazine (17.9 mg, 0.14 mmol),ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (26.8 mg,0.14 mmol), 1-hydroxy-7-azabenzotriazole (11.3 mg, 0.08 mmol) anddiisopropylethylamine (37 μL, 0.21 mmol) in THF (2.3 mL) and DMF (0.4mL) was heated to 60° C. for 3.25 hr. The mixture was cooled to rt. andconcentrated in vacuo on a speed vac. The residue was purified usingsilica gel column chromatography (5% acetone in dichloromethane followedby 1% and 2% methanol in dichloromethane) to afford the titled product(34 mg, 75%) as a light tan solid: LC/MS RT=1.90 min; mass spectrum(M+H)⁺=516.45.

EXAMPLE 364-Acetyl-1-[5-[[2-[N-(6-chloro-2-methyl-pyrimidine-4-yl)amino]thiazol-5yl]thio]-2-methoxy-4-methylbenzoyl]piperazine

[0317]

[0318] Sodium hydride (43.9 mg, 1.83 mmol) was added to a solution of5-[[[3-[(4-acetylpiperazin-1-yl)carbonyl]4-methyl-6-methoxy]phenyl]thio]-2-aminothiazole(Example 34, part B: 250 mg, 0.61 mmol) and2-methyl-4,6-dichloropyrimidine (200 mg, 1.23 mmol). The mixture washeated to 50° C. for 16 hr, cooled to rt, and supplemental sodiumhydride (43.9 mg, 1.83 mmol) was added. The mixture was heated to 50° C.for an additional 3 hr, cooled to rt, and excess hydride was quenched bythe addition of glacial acetic acid. The mixture was concentrated invacuo, diluted with satd. aq. NaHCO₃ solution, and extracted withTHF-EtOAc mixture (4×). The organic extracts were combined, washed withsatd. aq. NaHCO₃ solution, brine, dried (NaSO₄), filtered, andconcentrated in vacuo to obtain a tan solid which was triturated withether-EtOAc (4:1) to obtain the titled compound (260 mg, 80%) as a lighttan solid.

EXAMPLE 374-Acetyl-1-[5-[[2-[N-(6-N,N-dimethylaminoethylamino-2-methyl-pyrimidin-4-yl)amino]thiazol-5-yl]thio]-2-methoxy-4-methylbenzoyl]piperazine

[0319]

[0320] A solution of4-acetyl-1-[5-[[2-[N-(6-chloro-2-methyl-pyrimidin-4-yl)amino]thiazol-5-yl]thio]-2-methoxy-4-methylbenzoyl]piperazine(Example 36: 10 mg, 0.019 mmol), N,N-dimethylethylenediamine (10 μL,0.094 mmol), and 4-dimethylaminopyridine (2.32 mg, 0.019 mmol) indioxane (1 mL) was heated to 100 ° C. in a sealed vial for 16 hr. Themixture was purified using reversed phase automated preparative HPLC(conditions: YMC 20×100 mm column, 10 min gradient starting from 90%solvent A (10% MeOH, 90% H₂O, 0.1% TFA) and 10% solvent B (90% MeOH, 10%H₂O, 0.1% TFA) and final solvent:90% solvent B and 10% solvent A, flowrate 20 mL/min, λ=220 nM) to obtain the titled compound as a TFA salt(14 mg, 36% yield, tan solid): LC/MS RT=1.34 min; mass spectrum(M+H)⁺=585.16.

EXAMPLE 38

[0321]

[0322] A.2-Amino-5-[(5-carbomethoxy-4-methoxy-2-methylphenyl)thio]thiazole

[0323] To a suspension of the compound described in Example 34, part A(2.00 g, 6.75 mmol) in MeOH (100 mL) was added HCl in diethyl ether (2.0M, 10 mL) at rt. The mixture was heated at reflux overnight before MeOHwas removed under vacuum. To the residue was added water (50 mL). Theresulting mixture was adjusted to pH 12 with 1 N NaOH solution and thenextracted with EtOAc (4×40 mL). The combined extract was washed withwater and brine, and dried over anhydrous MgSO₄. Evaporation of solventunder vacuum provided the titled compound (1.73 g, 82% yield) as a tansolid.

[0324] B.2-[[(Cyclopropyl)carbonyl]amino]-5-[(5-carbomethoxy-4-methoxy-2-methylphenyl)thio]thiazole

[0325] A mixture of the compound from part A (1.73 g, 5.57 mmol),cyclopropylcarboxylic acid (95%, 0.69 mL, 8.28 mmol),1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.90 g,9.91 mmol), and 4-dimethylaminopyridine (0.070 g, 0.57 mmol) in CH₂Cl₂(120 mL) was heated at reflux overnight. The mixture was cooled to rt,diluted with CH₂Cl₂ (50 mL), and washed with water, 1 N HCl solution, 1N NaOH solution, water, and brine. The organic fraction was then driedover anhydrous MgSO₄. Evaporation of solvent under vacuum provided thetitled compound (1.91 g, 90% yield) as a beige solid.

[0326] C.2-[[(Cyclopropyl)carbonyl]amino]-5-[(5-carboxy-4-methoxy-2-methylphenyl)thio]thiazole

[0327] A mixture of the compound from part B (0.550 g, 1.45 mmol) and 1N NaOH (4.4 mL, 4.4 mmol) in THF (20 mL) was heated at reflux for 5 hr.Solvent was removed under vacuum, and the residue was acidified to pH 2with 1 N HCl. The resulting precipitate was collected by suctionfiltration, washed with water, and dried over drierite under vacuum toafford the titled compound (0.484 g, 92% yield) as a beige solid.

[0328] D.2-[[(Cyclopropyl)carbonyl]amino]-5-[(4-methoxy-2-methyl-5-piperazinylcarboamidophenyl)thio]thiazole

[0329] A solution of the compound from part C (0.252 g, 0.690 mmol.),piperazine (0.300 g, 3.60 mmol),(benzotriazol-1yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP, 0.622 g, 1.40 mmol) and N-methylmorpholine (0.38 mL, 3.5 mmol) inDMF (7.0 mL) was heated in an oil bath at 65 ° C. for 2 hr. Aftercooling to room temperature, the reaction mixture was diluted with EtOAcand washed with water (2×). The organic layer was dried over sodiumsulfate, filtered, and concentrated in vacuo to give the first crop ofproduct (0.0805 g, 27% yield). The aqueous layers were combined andextracted with dichloromethane (5×). The organic layers were combined,dried over sodium sulfate, filtered and concentrated in vacuo. Silicagel chromatography using dichloromethane:methanol:acetic acid(10:0.4:0.2) as eluent afforded the second crop of product (0.1860 g,62% yield) as a white solid: LC/MS (M+H)⁺=433.56.

[0330] E.2-[[(Cyclopropyl)carbonyl]amino]-5-[[(4-methoxy-2-methyl-5-[[(4-tert-butoxycarbonylamino)aceto]piperazinylcarboxamido]phenyl]thio]thiazole

[0331] A mixture of the compound from part D (46.5 mg, 0.107 mmol),N-Boc-glycine (38.5 mg, 0.22 mmol), BOP (92.9 mg, 0.21 mmol), andN-methylmorpholine (0.060 mL, 0.55 mmol) in DMF (0.5 mL) wasmechanically shaken at 65° C. overnight. The reaction mixture wasdiluted with MeOH (0.5 mL), purified using preparative HPLC andlyophilized to give the titled compound (51.6 mg, 82% yield) as a whitepowder.

[0332] F. Title Compound

[0333] To a solution of the compound from part E (40.1 g, 0.068 mmol) indichloromethane (1.0 mL) under nitrogen at 0° C. was addedtrifluoroacetic acid (1.0 mL). After 3 hr, the reaction mixture wasconcentrated in vacuo and triturated with diethyl ether to give thedesired product (30.8 mg, 75% yield) as a white solid: LC/MS(M+H)⁺=490.21.

EXAMPLE 39

[0334]

[0335] A mixture of2-[[(cyclopmopyl)carbonyl]amino]-5-[(4-methoxy-2-methyl-5-piperazinylcarboamidophenyl)thio]thiazole(Example 38, part D: 46.5 mg, 0.107 mmol), N-methylglycine (19.6 mg,0.22 mmol), BOP (92.9 mg, 0.21 mmol), and N-methylmorpholine (0.060 mL,0.55 mmol) in DMF (0.5 mL) was mechanically shaken at 65° C. overnight.The reaction mixture was diluted with MeOH (0.5 mL), purified usingpreparative HPLC, and lyophilized to give the title compound as a whitepowder TFA salt (27.3 mg, 41% yield): LC/MS (M+H)⁺=504.14.

EXAMPLE 40

[0336]

[0337] This material was prepared in the same manner as Example 39:LC/MS (M+H)⁺=518.22.

EXAMPLE 41

[0338]

[0339] A mixture of2-[[(cyclopropyl)carbonyl]amino]-5-[(4-methoxy-2-methyl-5-piperazinylcarboamidophenyl)thio]thiazole(Example 38, part D: 20.0 mg, 0.0549 mmol), 1-(2-pyrimidyl)piperazine(18.0 mg, 0.110 mmol), BOP (36.4 mg, 0.0823 mmol), andN-methylmorpholine (0.027 mL, 0.246 mmol) in DMF (0.5 mL) was stirred at55° C. overnight. The reaction mixture was diluted with MeOH (0.5 mL)and purified using preparative HPLC. The appropriate fractions werecombined and concentrated, and the pH adjusted to 12 with 1 N NaOHfollowed by extraction with CH₂Cl₂ (3×20 mL). The combined extract wasdried over anhydrous MgSO₄. Evaporation of solvent under vacuum providedthe desired product (20 mg, 71% yield) as a white solid: LC/MS(M+H)⁺=511.17.

EXAMPLE 42

[0340]

[0341] This material was prepared in the same manner as Example 41:LC/MS (M+H)⁺=511.15.

EXAMPLE 43

[0342]

[0343] A.2-Amino-5-[(4-methoxy-2-methyl-5-[[(morpholinyl)carboxamido]phenyl]thio]thiazole

[0344] A mixture of2-Amino-5-[(5-carboxy-4-methoxy-2methylpheny)thio]thiazole (Example 34,part A: 1.00 g, 3.37 mmol), morpholine (0.59 mL, 6.74 mmol), BOP (2.24g, 5.06 mmol), and N-methylmorpholine (1.60 mL, 14.6 mmol) in DMF (10mL) was heated at 60° C. for 2.5 hr. The solution was diluted with EtOAc(150 mL), then washed with water (3×40 mL) and brine (40 mL). Theaqueous layer was extracted with EtOAc (2×50 mL) and the combinedorganic layer was dried over anhydrous MgSO₄. The solution wasconcentrated under vacuum, and the residue purified using flashchromatography (silica gel, 6% MeOH/CHCl₃) to give the titled compound(0.935 g, 76% yield) as a tan solid.

[0345] B.2-[[(5-Formyl-2-pyrroly)carbonyl]amino]-5-[[(morpholinyl)carboxamido]phenyl]thio]thiazole

[0346] To a suspension of 5-formyl-2-pyrrole carboxylic acid (0.320 g,2.30 mmol) in CH₂Cl₂ (25 mL) at ° C. was added thionyl chloride, and theresulting mixture heated at reflux for 1.5 hr. The solvent and excessthionyl chloride was evaporated under vacuum. Residual thionyl chloridewas removed by adding toluene (1 mL) and concentrating the mixture todryness under vacuum. The residue was dissolved in CH₂Cl₂ (25 mL), andto the resulting solution was added a solution of the compound of part A(0.927 g, 2.54 mmol) and pyridine (1.1 mL, 13.6 mmol) in CH₂Cl₂ (30 mL).

[0347] The mixture was heated at reflux for 2.5 hr before it wasconcentrated to dryness under vacuum. To the solid residue was added 0.5N HCl (40 mL) and the mixture was well stirred for 10 min. Theprecipitate was collected by suction filtration, washed with water, anddried over drierite under vacuum to give the title compound (0.880 g,71% yield) as a tan solid.

[0348] C.2-[[(5-Hydroxymethyl-2-pyrrolyl)carbonyl]amino]-5-[[(morpholinyl)carboxamido]phenyl]thio]thiazole

[0349] To a suspension of the compound from part B (0.400 g, 0.822 mmol)in DMF (40 mL) and MeOH (20 mL) was added NaBH₄ (0.622 g, 16.4 mmol) at0° C. in one portion. The mixture was stirred at rt. overnight, afterwhich period the heterogeneous mixture became a clear solution. Thereaction was quenched with water (5 mL), and the resulting solution wasconcentrated to approximately 20 mL. The residue was diluted with water(40 mL), extracted with EtOAc (3 ×40 mL) and CH₂Cl₂ (3×40 mL). Thecombined organic layer was concentrated under vacuum. To the residue wasadded Et₂O (20 mL). The resulting precipitate was collected byfiltration, washed with water, and dried over drierite under vacuum toprovide the title product (0.226 g, 56% yield) as a beige solid.

[0350] D. Title Compound

[0351] A mixture of the compound from part C (80 mg, 0.164 mmol) andthionyl chloride (2 mL) was heated at 60° C. for 1.5 hr. The excessthionyl chloride was evaporated under vacuum. Residual thionyl chloridewas removed by adding toluene (1 mL) and concentrating the mixture todryness under vacuum. The residue was dissolved in anhydrous DMF (2 mL),and to the resulting solution was added NH₃/MeOH (7 M solution, 7 mL, 7mmol). The mixture was heated in a sealed tube at 55° C. for 16 hr.After cooling to rt, the reaction mixture was poured into 1 N HClsolution (15 mL). The resulting mixture was extracted with EtOAc (3×20mL). The aqueous solution was adjusted to pH 12 with 10% NaOH solution,and extracted with EtOAc (4×30 mL). The combined extract was dried overanhydrous MgSO₄, and concentrated under vacuum. The residue was purifiedusing preparative HPLC and lyophilized to provide the titled product(3.0 mg, 3% yield) as a white powder, TFA salt: LC/MS (M+H)⁺=488.14.

EXAMPLE 44

[0352]

[0353] To a mixture of the compound of Example 43, part B (40 mg, 0.082mmol) and MeNH₂/THF (2.0 M solution, 0.16 mL, 0.32 mmol) in anhydrousDMF (8 mL) at rt. was added NaBH(OAc)₃ (71 mg, 0.32 mmol) in oneportion. The mixture was stirred at rt. for 6 hr before supplementaryNaBH(OAc)₃ (35 mg, 0.16 mmol) was added. The mixture was allowed to stirat rt. overnight before it was quenched with saturated NaHCO₃ solution(10 mL). The mixture was then diluted with EtOAc (100 mL) and washedwith water (3×25 mL). The aqueous solution was extracted with EtOAc (50mL). The combined organic phase was washed with 10% LiCl solution (35mL), and concentrated under vacuum. The residue was purified usingpreparative HPLC and lyophilized to provide the title product (22.7 mg,45% yield) as a white powder, TFA salt: LC/MS (M+H)⁺=502.17.

EXAMPLE 45

[0354]

[0355] This material was prepared in a similar manner as Example 44:LC/MS (M+H)⁺=516.2.

EXAMPLE 46

[0356]

[0357] This material was prepared in the same manner as Example 44:LC/MS (M+H)⁺=532.19.

EXAMPLE 47

[0358]

[0359] To a mixture of the compound from Example 43, part B (20 mg,0.041 mmol) and 1,2-dimethylpropylamine (7.2 mg, 0.082 mmol) inanhydrous DMF (4 mL) at rt. was added NaBH(OAc)₃ (17 mg, 0.082 mmol) inone portion. The mixture was stirred at rt. for 20 hr beforesupplementary NaBH(OAc)₃ (26 mg, 0.12 mmol) was added. The mixture wasallowed to stir at rt. for an additional 24 hr before it was quenchedwith saturated NaHCO₃ solution (10 mL). The resulting mixture wasdiluted with EtOAc, washed with water (2×) and brine, and concentratedunder vacuum. The residue was dissolved in MeOH (5 mL), and to theresulting solution was added 1 N HCl (2 mL). The mixture was then heatedat reflux for 1.5 hr. After cooling to rt, the solution was adjusted topH 12 with 1N NaOH solution, diluted with water (5 mL), and extractedwith EtOAc (3×). The combined extract was washed with brine andconcentrated under vacuum. The residue was purified using preparativeHPLC and lyophilized to provide the desired product (4.6 mg, 17% yield)as a white powder, TFA salt: LC/MS (M+H)⁺=558.34.

EXAMPLE 48

[0360]

[0361] This material was prepared in the same manner as Example 44:LC/MS (M+H)⁺=530.37.

EXAMPLE 49

[0362]

[0363] A mixture of 2-pyrrolecarboxylic acid (6.5 mg, 0.058 mmol) andthionyl chloride (0.8 mL, 11.0 mmol) was heated at 60° C. for 1.5 hr.The excess thionyl chloride was evaporated under vacuum. Residualthionyl chloride was removed by adding toluene (1 mL) and concentratingthe mixture to dryness under vacuum. The residue was dissolved in CH₂Cl₂(1.5 mL), and to the resulting solution was added the compound ofExample 34, part B (20 mg, 0.049 mmol) in CH₂Cl₂ (1.5 mL), followed bythe addition of pyridine (0.080 mL, 0.99 mmol). The mixture was heatedat reflux for 2 hr before it was concentrated under vacuum. The residuewas purified using preparative HPLC to give the desired product (20.5mg, 84% yield) as a pale yellow solid: LC/MS (M+H)⁺=500.33.

EXAMPLE 50

[0364]

[0365] This compound was prepared from the compound described in Example3, part E using previously described coupling conditions: LC/MS(M+H)⁺=452.3.

[0366] B.

[0367] A mixture of the compound from part A (112 mg, 0.25 mmol),(methoxycarbonylsulfamoyl)triethylammoniumhydroxide, inner salt (150 mg,0.63 mmol) and triethylamine (0.09 mL, 0.63 mmol) in THF (3 mL) wasstirred for 2 hr at rt. After partitioning the reaction mixture betweenEtOAc (25 mL) and water (25 mL), the organic layer was washed with water(25 mL) and brine (25 mL). The organic layer was dried over MgSO₄ andconcentrated to afford 88 mg (82%) of the titled compound as a whitesolid: LC/MS (M+H)⁺=436.37.

[0368] C.

[0369] A mixture of the compound of part B (80 mg, 0.18 mmol) andtributyltin azide (150 mg, 0.45 mmol) in toluene (3 mL) was heated to100° C. for 24 hr. A supplemental amount of tributyltin azide (150 mg,0.45 mmol) was added and the mixture was heated at 100° C. for 24 hr.The reaction mixture was loaded onto a 1×5 cm silica gel column, whichwas eluted with 50 mL hexane, 50 mL of methylene chloride and 50 mL of10% methanol/methylene chloride. Concentration of product containingfractions and trituration with ethyl ether afforded 12 mg (14%) of thetitled compound as a tan solid: LC/MS (M+H)⁺=479.37.

EXAMPLE 51

[0370]

[0371] A mixture of the compound described in Example 3, part E (15 mg,0.044 mmol), methanesulfonamide (5 mg, 0.05 mmol), EDCI (10 mg, 0.05mmol) and 4-dimethylaminopyridine (7 mg, 0.055 mmol) in methylenechloride (0.5 mL) was stirred 48 hr at rt. The reaction mixture waspartitioned between EtOAc (5 mL) and saturated potassium bisulfatesolution (5 mL). After washing with water (5 mL) and brine (5 mL), theorganic layer was dried over magnesium sulfate and concentrated toafford 11 mg (61%) of the titled compound as a white powder: MS(M+H)⁺=421.22.

EXAMPLES 52-455

[0372] Using methods similar to those previously described, thefollowing compounds 52 through 455 were synthesized. Ex. MS No.Structure (M + H)⁺ 52

555.08 53

441.4 54

445.04 55

525.21 56

551.12 57

493.43 58

524.32 59

539.28 60

580.38 61

567.16 62

485.34 63

479.37 64

540.14 65

540.53 66

499.45 67

594.36 68

554.31 69

513.27 70

626.45 71

640.32 72

599.29 73

573.28 74

612.46 75

574.38 76

624.39 77

510.43 78

510.34 79

541.35 80

582.42 81

554.98 82

583.37 83

597.36 84

568.47 85

582.32 86

610.35 87

569.18 88

583.29 89

551.11 90

603.97 91

475.4 92

491.57 93

504.58 94

489.6 95

489.58 96

543.52 97

491.28 98

519.5 99

595.19 100

493.38 101

465.29 102

452.12 103

516.2 104

544.32 105

568.28 106

598.18 107

596.35 108

626.54 109

568.26 110

608.5 111

564.43 112

594.51 113

608.46 114

634.26 115

610.58 116

580.26 117

596.58 118

608.19 119

594.34 120

623.47 121

579.35 122

581.36 123

607.51 124

584.18 125

582.4 126

566.39 127

585.22 128

585.17 129

596.65 130

596.59 131

470.4 132

580.26 133

594.4 134

644.4 135

644.35 136

568.24 137

568.43 138

598.18 139

610.26 140

610.24 141

630.35 142

580.4 143

623.26 144

622.43 145

644.28 146

644.2 147

630.19 148

598.19 149

598.2 150

634.3 151

634.32 152

594.34 153

600.22 154

552.3 155

610.31 156

608.3 157

582.26 158

582.24 159

596.35 160

604.38 161

660.12 162

614.11 163

566.27 164

624.27 165

624.18 166

524.14 167

582.17 168

510.09 169

610.49 170

583.21 171

525.14 172

585.18 173

571.19 174

566.22 175

581.24 176

511.12 177

580.29 178

727.23 179

593.28 180

622.36 181

622.32 182

551.25 183

567.23 184

583.26 185

576.42 186

598.24 187

608.31 188

584.16 189

607.33 190

580.35 191

590.23 192

610.27 193

475.3 194

530.37 195

471.12 196

525.19 197

549.19 198

539.53 199

484.25 200

498.19 201

638.39 202

624.54 203

638.48 204

622.33 205

632.34 206

662.22 207

582.19 208

612.35 209

612.34 210

568.19 211

527.19 212

485.1 213

514.97 214

484.06 215

614.32 216

526.23 217

614.2 218

514.25 219

528.25 220

611.31 221

535.31 222

503.25 223

586.37 224

579.26 225

593.35 226

597.43 227

597.33 228

607.21 229

583.57 230

500.33 231

572.33 232

572.34 233

558.34 234

379.39 235

364.1 236

365.06 237

529.19 238

447.21 239

461.33 240

511.17 241

502.17 242

532.19 243

483.24 244

421.22 245

489.20 246

504.14 247

518.22 248

590.21 249

511.15 250

490.21 251

488.14 252

625.28 253

611.30 254

651.19 255

651.17 256

612.14 257

612.14 258

419.2 259

420.22 260

441.3 261

483.4 262

454.3 263

439.4 264

535.3 265

483.4 266

499.4 267

453.4 268

516.4 269

407.3 270

453.4 271

441.4 272

456.4 273

511.5 274

535.4 275

567.3 276

524.3 277

441.4 278

507.3 279

409.3 280

427.3 281

441.4 282

483.4 283

530.4 284

462.4 285

453.4 286

502.4 287

452.3 288

545.4 289

487.4 290

513.3 291

554.2 292

534.3 293

559.4 294

566.4 295

501.1 296

498.4 297

535.2 298

491.4 299

499.2 300

543.3 301

491.4 302

495.4 303

477.4 304

473.3 305

410.3 306

486.2 307

449.2 308

431.3 309

468.4 310

397.3 311

425.3 312

411.3 313

425.3 314

452.4 315

429.4 316

571.1 317

521.4 318

442.2 319

500.4 320

468.4 321

517.1 322

453.4 323

441.4 324

598.1 325

488.3 326

489.3 327

591.6 328

589.3 329

453.3 330

413.16 331

512.21 332

499.14 333

475.2 334

453.22 335

443.38 336

558.22 337

597.52 338

443.24 339

597.37 340

611.47 341

371.24 342

399.29 343

427.32 344

415.31 345

401.34 346

456.35 347

412.19 348

397.59 349

438.59 350

516.45 351

477.44 352

495.01 353

535.98 354

470.09 355

455.07 356

537.29 357

537.33 358

471.05 359

471.44 360

486.42 361

541.08 362

525.12 363

555.11 364

539.34 365

524.94 366

496.92 367

534.01 368

492.99 369

484.07 370

514.13 371

499.12 372

514.06 373

500.33 374

584.12 375

599.18 376

470.05 377

484.09 378

535.96 379

440.1 380

443.06 381

485.36 382

514.07 383

512.19 384

468.13 385

471.16 386

500.1 387

515.28 388

533.21 389

514.29 390

584.34 391

598.36 392

625.42 393

619.38 394

585.12 395

599.13 396

558.1 397

583.11 398

586.28 499

608.27 400

627.3 401

641.34 402

598.29 403

542.25 404

470.1 405

586.25 406

611.17 407

599.62 408

639.29 409

570.23 410

597.25 411

585.24 412

626.31 413

441.3 414

524.34 415

493.34 416

551.35 417

533.33 418

576.35 419

436.37 420

444.34 421

554.35 422

430.32 423

479.37 424

540.32 425

527.09 426

513.5 427

457.06 428

443.49 429

457.44 430

467.30/ 469.30 431

443.31 432

612.18/ 614.18 433

569.42 434

541.4 435

473.45 436

618.06 437

569.4 438

583.4 439

555.1 440

555.1 441

567.29 442

638.31 443

570.3 444

571.28 445

557.33 446

585.39 447

571.27 448

598.15 449

498.19 450

540.19 451

433.56 452

475.27 453

533.56 454

465.59 455

507.24

We claim:
 1. A compound of formula I

including diastereomers, enantiomers and salts thereof where Q₁ isthiazolyl; Q₂ is aryl or heteroaryl optionally independently substitutedwith one or more substituents R_(1a); Z is (1) —O—, (2) —S—, (3) —NR₄—,(4) —CR₄R₅—, (5) —CR₄R₅—O—CR_(4a)R_(5a)—, (6)—CR₄R₅—NR_(4b)—CR_(4a)R_(5a)—, (7) —CR₄R₅—S—CR_(4a)R_(5a)—, (8)—CR₄R₅—O—, (9) —O—CR₄R₅—, (10) —CR₄R₅—NR_(4b)—, (11) —NR_(4b)—CR₄R₅—,(12) —CP₄R₅—S—, (13) —S—CR₄R₅—, (14) —S(O)_(q)— where q is 1 or 2, (15)—CR₄R₅—S(O)_(q)—, or (16) —S(O)_(q)—CR₄R₅—; R₁ and R_(1a) areindependently (1) hydrogen or R₆, (2) OH or  OR₆, (3) —SH or —SR₆, (4)—C(O)_(q)H, —C(O)_(q)R₆, or —O—C(O)_(q)R₆, (5) —SO₃H or —S(O)_(q)R₆, (6)halo, (7) cyano, (8) nitro, (9) —Z—NR₇R₈, (10) —Z—N(R₉)—Z₅—NR₁₀R₁₁, (11)—Z₄—N(R₁₂)—Z₅—R₆, or (12) —P(O)(OR₆)₂; R₂ and R₃ are each independentlyH, —Z₄—R_(6a), or —NR_(7a)R_(8a) R₄, R_(4a), R_(4b), R₅ and R_(5a) areeach independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, orheteroarylalkyl; R₆, R_(6a), R_(6b) and R_(6c) are independently alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, eachof which is unsubstituted or substituted with Z₁, Z₂ and one or moregroups Z₃, R₇, R_(7a), R₈, R_(8a), R₉, R₁₀, R₁₁ and R₁₂ (1) are eachindependently hydrogen, or —Z₄R_(6b); or (2) R₇ and R₈, or R_(7a) andR_(8a) may together be alkylene, alkenylene, or heteroalkylene,completing a 3- to 8-membered saturated or unsaturated ring with thenitrogen atom to which they are attached, which ring is unsubstituted orsubstituted with Z₁, Z₂ and one or more groups Z₃, or (3) any two of R₉,R₁₀ and R₁₁ may together be alkylene, alkenylene or heteroalkylenecompleting a 3- to 8-membered saturated or unsaturated ring togetherwith the nitrogen atoms to which they are attached, which ring isunsubstituted or substituted with one or more Z₁, Z₂ and Z₃; Z₁, Z₂ andZ₃ are each independently (1) hydrogen or Z₆, (2) —OH or —OZ₆, (3) —SHor —SZ₆, (4) —C(O)_(q)H, —C(O)_(q)Z₆, or —O—C(O)_(q)Z₆, (5) —SO₃H,—S(O)_(q)Z₆, or S(O)_(q)N(Z)Z₆, (6) halo, (7) cyano, (8) nitro, (9)—Z₄—NZ₇Z₈, (10) —Z₄—N(Z₉)—Z₅—NZ₇Z₈, (11) —Z₄—N(Z₁₀)—Z₅—Z₆, (12)—Z₄-N(Z₁₀)—Z₅—H, (13) oxo, (14) any two of Z₁, Z₂, and Z₃ on a givensubstituent may together be alkylene or alkenylene completing a 3- to8-membered saturated or unsaturated ring together with the atoms towhich they are attached; or (15) any two of Z₁, Z₂, and Z₃ on a givensubstituent may together be —O—(CH₂)_(q)—O—; Z₄ and Z₅ are eachindependently (1) a single bond, (2) —Z₁₁—S(O)_(q)—Z₁₂—, (3)—Z₁₁—C(O)—Z₁₂—, (4) —Z₁₁—C(S)—Z₁₂—, (5) —Z₁₁—O—Z₁₂—, (6) —Z₁₁—S—Z₁₂—,(7) —Z₁₁—O—C(O)—Z₁₂—, (8) —Z₁₁—C(O)—O—Z₁₂—; or (9) alkyl Z₆ and Z_(6a)are independently (i) alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl,aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, orheterocycloalkyl; (ii) a group (i) which is itself substituted by one ormore of the same or different groups (i); or (iii) a group (i) or (ii)which is independently substituted by one or more of the groups (2) to(15) of the definition of Z₁; Z₇, Z₈, Z₉ and Z₁₀ (1) are eachindependently hydrogen or —Z₄—Z_(6a); (2) Z₇ and Z₈ may together bealkylene, alkenylene, or heteroalkylene completing a 3- to 8-memberedsaturated or unsaturated ring together with the atoms to which they areattached, which ring is unsubstituted or substituted with one or moreZ₁, Z₂ and Z₃, or (3) Z₇ or Z₈, together with Z₉, may be alkylene,alkenylene, or heteroalkylene completing a 3- to 8-membered saturated orunsaturated ring together with the nitrogen atoms to which they areattached, which ring is unsubstituted or substituted with one or moreZ₁, Z₂ and Z₃; Z₁₁ and Z₁₂ are each independently (1) a single bond, (2)alkylene, (3) alkenylene, or (4) alkynylene; provided that said compoundis other than (a) a compound of formula X

where Z_(a) is —CR₄R₅—, —NR₄—, or —NR₄—CR₄R₅—; Q₂ is as defined above;R_(a1) is alkyl, alkenyl, cylcoalkyl, heterocyclo, aryl, aralkyl or—NR_(7a1)R_(8a1); R_(7a1) is alkyl, cycloalkyl, heterocylco, aryl,—C(O)aryl, or aralkyl; and R_(8a1) is H, alkyl, alkenyl or alkynl; orR_(7a), and R_(7a1) combine to form a heterocylo group; (b) a compoundof formula XI

where Z_(b) is —CR₄R₅—, —NR₄—, or —NR₄—CR₄R₅—; Q_(2b) is aryl R_(b1) isH, alkyl optionally substituted with hydroxy, alkoxy, amino, alkylaminoor dialkylamino; L is phenyl or heteroaryl; R_(b2) is —NR_(b3)R_(b4), or—N(H)C(O)R_(b5); R_(b3) and R_(b4) are each independently H, cycloalkyl,alkyl or aryl; or R_(b3) and R_(b4) together with the nitrogen atom towhich they are attached combine to form 4-morpholinyl, 1-piperazinyl,N-alkyl-piperazinyl, N-aryl-piperazinyl, N-arylalkyl-piperazinyl,piperidinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolyl, or3-azabicyclo[3.2.2]nonyl; and R_(b5) is carboxy, alkyl, perfluoroalkyl,alkynyl, aryl, 2-oxo-pyrrolidinyl or piperidinyl; (c) a compound offormula XIIa or XIIb

where Q₂ is as defined above; Z_(c) is CH₂; and R_(c1) is aryl orheterocyclo; (d) a compound of formula XIII

where Z_(d) is CH₂; Q_(2d) is aryl; R_(d1) is —C(O)NR_(d7)R_(d8)  (1)

where c and d are zero to 1 providing c and d are not simultaneouslyzero; e is zero to 5; and f is zero to 3; or

where c₁, d₁, f₁, g₁, k₁, l₁ and m₁ are each independently zero or 1,where c₁, f₁ and g₁ are not simultaneously zero, and where m₁ is notzero when f₁ or g₁ is 1; i₁ is zero or 1, where k₁ and l₁ are zero wheni₁ is zero; e₁ is zero to 3 h₁ is zero to 5; j₁ is zero to 2; and thesum of e₁, h₁ and j₁ is 2 to 7; A is —O—, —S—, —CH═CH—, or —N(R_(d6))—;R_(d2) and R_(d3) are independently H, alkyl, cycloalkyl or heteroaryl;R_(d4) is H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heteroaryl or heteroarylalkyl; R_(d5) is H, alkyl or cycloalkyl; R_(d6)is H, aryl, aralkyl, heteroaryl, hetercycloalkyl, carboxyalkyl, alkyl,cycloalkyl, —C(O)₂alkyl, —C(O)₂aralkyl, —C(O)alkyl, alkylsulphonyl,arylsulfonyl or heteroarylsulfonyl; R_(d7) and R_(d8) together with thenitrogen atom to which they are attached combine to from a 5 to8-membered saturated or unsaturated ring substituted with the group X;and X is

where g is zero to 4; i is zero or 1, with k being zero when i is zero;the sum of h, i and j is ≧1 and ≧4; k and m are independently zero or 1,with n being other than zero when m is 1; and the sum of 1, m and n is≧2 and ≧5; (e) a compound of formula XIV

where Z is —S—, S(O)_(q), or —CH₂—S(O)_(q)—; Q_(2e) is (2) aryloptionally substituted with one group selected from halo, hydroxy,alkoxy nitro, —NH₂, -alkyl(NH₂), -C(O)NH₂, -alkylC(O)NH₂ or-arylC(O)NH₂; or (3) heteroaryl optionally substituted with one groupselected from alkyl, hydroxy, haloalkyl or NH₂; R_(e1) is H, alkyl,hydroxyalkyl, halogen or carboxy; and R_(e2) is H, —C(O)alkyl, —SO₂alkylor —C(O)phenyl optionally substituted with halogen; (f) a compound offormula XVa or XVb

where Z_(f) is —CR₄R₅—, —O—CR₄R₅, or —NR₄—, Z_(f*) is —CR₄R₅—; Q_(2f) isaryl or heteroaryl; R_(f1) is alkyl, aryl, heteroaryl, or cycloalkyl;R_(f1*) is H, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl,heterocyclo, amino-substituted alkoxy, nitro, hydroxy, or NH₂; R_(f2) isH, alkyl, aryl, heteroaryl, or cycloalkyl; and R_(f3) is H, alkyl,cycloalkyl, aryl, halo, CF₃, or heterocyclo; (g) a compound of formulaXVI

where Z_(g) is —NH— or —NH—CR₄R₅—; Q_(2g) is aryl, heteroaryl; X is C orN Q is a divalent radical containing 2 or 3 ring atoms eachindependently selected from C, N, O, S, CR_(g1), NR_(g1), which togetherwith C* and N* form a 5 or 6-membered aromatic or nonaromatic ring;R_(g1) is hydroxy, halo, cyano, nitro, alkyl, alkenyl, cycloalkyl,non-aromatic heterocyclo, aryl, heteroaryl, or —C(O)R_(g2); or R_(g1)cycloalkyl, heterocyclo or aryl that is fused to Q; R_(g2) is H, alkyl,cycloalkyl, non-aromatic heterocyclo, aryl, heteroaryl or —OC(O)R_(g3);R_(g3) is H, alkyl, cycloalkyl, non-aromatic heterocyclo, aryl,heteroaryl or —C(O)NR_(g4)R_(g5); R_(g4) and R_(g5) are independently H,alkyl, cycloalkyl, heterocyclo, aryl or —C(R_(g6))═NR_(g7); R_(g6) is H,alkyl, cycloalkyl, heterocyclo, aryl, amino, alkylamino, dialkylamino or—SO₂R_(g8); R_(g7) is H, alkyl, cycloalkyl, heterocyclo, arylheteroaryl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, or—C(O)amino; R_(g8) is alkyl, cycloalkyl, heterocyclo, aryl or—SO₂NR_(g9)R_(g10); R_(g9) and R_(g10) are independently H, alkyl,cyclcoalkyl, heterocyclo, aryl, or —OR_(g11); R_(g11) is alkyl,cycloalkyl, heterocyclo, aryl, —(O)R_(g2), —OC(O)R_(g3),—C(O)NR_(g4)R_(g5), —NR_(g12)R_(g13), or —SR_(g14); R_(g12) is H, alkyl,cycloalkyl, heterocyclo, aryl, hydroxy, alkoxy, amino, —C(O)R_(g2),—OC(O)R_(g3), —C(O)NR_(g4)R_(g5), or —C(R_(g6))═NR_(g7); R_(g13) is H,alkyl, cycloalkyl, heterocyclo, aryl, —C(O)R_(g2), —OC(O)R_(g3),—C(O)NR_(g4)R_(g5), —C(R_(g6))═NR_(g7), —SO₂R_(g8), or—SO₂NR_(g9)R_(g10); and R_(g14) is H, alkyl, cycloalkyl, heterocylco,aryl or —C(O)NR_(g4)R_(g5); or (h) a compound of formula XVII

where Z_(h) is —S— or —S(O)_(q)—CR₄R₅—; and Q_(2h) is heteroaryl
 2. Acompound of claim 1 having the following formula II


3. A compound of claim 1 wherein Q₂ is optionally substituted phenyl; Zis selected from —S—, —CR₄R₅—S—, —S—CR₄R₅—, —CR₄R₅—O—CR_(4a)R_(5a)—,CR₄R₅NR_(4b)—CR_(4a)R_(5a)—, —CR₄R₅—, —CR₄R₅—SO₂— or —CR₄R₅—S(O)—; R₂ ishydrogen or alkyl; and R₃ is H, —Z₄R_(6a) or —Z₄NR_(7a)R_(8a).
 4. Acompound of claim 3 wherein the Q₂ phenyl is independently substitutedwith alkyl, hydroxy, alkoxy, haloalkoxy, halo, nitro, —C(O)_(q)R₆,—C(O)_(q)H, —Z—NR₇R₈, —Z₄—N(R₁₂)—Z₅—Z₆, or —Z₄—N(R₉)—Z₅—NR₁₀R₁₁).
 5. Acompound of claim 4 wherein R₃ is —ZR_(6a).
 6. A compound of claim 5wherein Z is —S—, —CR₄R₅—S—, or —S—CR₄R₅—.
 7. A compound of formulaIIIa, IIIb or IIIc

including diastereomers, enantiomers and salts thereof where Z is (1)—O—, (2) —S—, (3) —CR₄R₅—O—CR_(4a)R_(5a)—, (4)—CR₄R₅—NR_(4b)—CR_(4a)R_(5a) (5) —CR₄R₅—S—CR_(4a)R_(5a)—, (6) —CR₄R₅—O—,(7) —CR₄R₅—NR_(4b)—, (8) —CR₄R₅—S—, (9) —S—CR₄R₅—, (10) —S(O)_(q)—, (11)—CR₄R₅—S(O)_(q)—, or (12) —S(O)_(q)—CR₄R₅—; R₁, R_(1ab), R_(1ac) andR_(1ad) are independently (1) hydrogen or R₆, (2) —OH or —OR₆, (3) —SHor —SR₆, (4) —C(O)_(q)H, —C(O)_(q)R₆, or —O—C(O)_(q)R₆, where q is 1 or2, (5) —SO₃H or —S(O)_(q)R₆, (6) halo, (7) cyano, (8) nitro, (9)—Z₄—NR₇R₈, (10) —Z₄—N(R₉)—Z₅—NR₁₀R₁₁, (11) —Z₄—N(R₁₂)—Z₅—R₆, or (12)—P(O)(OR₆)₂; R_(1aa) is —C(O)_(q)H, —C(O)_(q)R₆, —Z₄—NR₇R₈,—Z₄—N(R₉)—Z₅—NR₁₀R₁₁ or —Z₄—N(R₉)—Z₅-R₆; R₂ and R₃ are eachindependently H, —Z₄—R_(6a), or —Z₄—NR_(7a)R_(8a); R₄, R_(4a), R₅ andR_(5a) are each independently hydrogen, alkyl, aryl, aralkyl,cycloalkyl, or heteroarylalkyl; R₆, R_(6a), R_(6b) and R_(6c) areindependently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, orheterocycloalkyl, each of which is unsubstituted or substituted with Z₁,Z₂ and one or more groups Z₃, R₇, R_(7a), R₈, R_(8a), R₉, R₁₀, R₁₁ andR₁₂ (1) are each independently hydrogen, or —Z₄R_(6b); or (2) R₇ and R₈,or R_(7a) and R_(8a) may together be alkylene, alkenylene, orheteroalkylene, completing a 3- to 8-membered saturated or unsaturatedring with the nitrogen atom to which they are attached, which ring isunsubstituted or substituted with Z₁, Z₂ and one or more groups Z₃, or(3) any two of R₉, R₁₀ and R₁₁ may together be alkylene, alkenylene orheteroalkylene completing a 3- to 8-membered saturated or unsaturatedring together with the nitrogen atoms to which they are attached, whichring is unsubstituted or substituted with one or more Z₁, Z₂ and Z₃; Z₁,Z₂ and Z₃ are each independently (1) hydrogen or Z₆ (2) —OH or —OZ₆, (3)—SH or —SZ₆, (4) —C(O)_(q)H, —C(O)_(q)Z₆, or —O—C(O)_(q)Z₆, (5) —SO₃H,—S(O)_(q)Z₆, or S(O)_(q)N(Z₉)Z₆, (6) halo, (7) cyano, (8) nitro, (9)—Z—NZ₇Z₈, (10) —Z₄—N(Z₉)—Z₅-NZ₇Z₈, (11) —Z₄—N(Z₁₀)—Z₅—Z₆, (12)—Z₄—N(Z₁₀)—Z₅—H, (13) oxo, (14) any two of Z₁, Z₂, and Z₃ on a givensubstituent may together be alkylene or alkenylene completing a 3- to8-membered saturated or unsaturated ring together with the atoms towhich they are attached; or (15) any two of Z₁, Z₂, and Z₃ on a givensubstituent may together be —O—(CH₂)_(q)—O—; Z₄ and Z₅ are eachindependently (1) a single bond, (2) —Z₁₁—S(O)_(q)—Z₁₂—, (3)—Z₁₁—C(O)—Z₁₂—, (4) —Z₁₁—C(S)—Z₁₂—, (5) —Z₁₁—O—Z₁₂—, (6) —Z₁₁—S—Z₁₂—,(7) —Z₁₁—O—C(O)—Z₁₂—-, (8) —Z₁₁—C(O)—O—Z₁₂—; or (9) alkyl Z₆ and Z_(6a)are independently (i) alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl,aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, orheterocycloalkyl; (ii) a group (i) which is itself substituted by one ormore of the same or different groups (i); or (iii) a group (i) or (ii)which is independently substituted by one or more of the groups (2) to(15) of the definition of Z₁; Z₇, Z₈, Z₉ and Z₁₀ (1) are eachindependently hydrogen or —Z₄—Z_(6a); (2) Z₇ and Z₈ may together bealkylene, alkenylene, or heteroalkylene completing a 3- to 8-memberedsaturated or unsaturated ring together with the atoms to which they areattached, which ring is unsubstituted or substituted with one or moreZ₁, Z₂ and Z₃, or (3) Z₇ or Z₈, together with Z₉, may be alkylene,alkenylene, or heteroalkylene completing a 3- to 8-membered saturated orunsaturated ring together with the nitrogen atoms to which they areattached, which ring is unsubstituted or substituted with one or moreZi, Z₂ and Z₃; Z₁₁ and Z₁₂ are each independently (1) a single bond, (2)alkylene, (3) alkenylene, or (4) alkynylene; provided said compound isother than a compound of formula XIV

where Z_(e)—S, S(O)_(q)—, or —CH₂—S(O)_(q)—; Q_(2e) is phenyl optionallysubstituted with one group selected from halo, hydroxy, alkoxy nitro,—NH₂, -alkyl(NH₂), —C(O)NH₂, -alkylC(O)NH₂ or -arylC(O)NH₂; R_(e1) is H,alkyl, hydroxyalkyl, halogen or carboxy; and R_(e2) is H, —C(O)alkyl,—SO₂alkyl or —C(O)phenyl optionally substituted with halogen.
 8. Acompound of claim 7 having the formula IIIa.
 9. A compound of claim 8where Z is —S—, —CR₄R₅—S—, or —S—CR₄R₅—; R₂ is hydrogen or alkyl; and R₃is -Z4Rra, where: (a) Z₄ is a single bond and R_(6a) is heteroaryloptionally substituted with one or more Z₁, Z₂ or Z₃; (b) Z₄ is —C(O)—and R_(6a) is (1) aryl optionally substituted with one or more Z₁, Z₂ orZ₃; (2) alkyl optionally substituted with one or more Z₁, Z₂ or Z₃; (3)cycloalkyl optionally substituted with one or more Z₁, Z₂ or Z₃; or (4)heterocyclo optionally substituted with one or more Z₁, Z₂ or Z₃; or (c)Z₄ is —C(O)—O— and R_(6a) is alkyl, cycloalkyl, aryl or aralkyl, any ofwhich may be optionally substituted with one or more Z₁, Z₂ or Z₃.
 10. Acompound of claim 9 wherein R_(1aa) is —C(O)R_(6a) or —Z₄—NR₇R₈; andR_(1ab), R_(1ac) and R_(1ad) are independently H, alkyl, hydroxy, nitro,halo, —OR₆, —NR₇R₈, —C(O)_(q)H or —C(O)_(q)R₆.
 11. A compound of claim10 wherein at least one of R_(1ab), R_(1ac) and R_(1ad) is other than H.12. A compound of claim 8 having the following formula IV

where one of R_(1ab), R_(1ac) and R_(1ad) is H and the other two areindependently alkyl, hydroxy, nitro, halo, —OR₆, —NR₇R₈, —C(O)_(q)H, or—C(O)_(q)R₆.
 13. A compound of claim 12 wherein one of R_(1ab), R_(1ac)and R_(1ad) is H and the other two are independently alkyl or —OR₆. 14.A compound of claim 13 wherein Z is —S— and R_(1c) is H.
 15. A compoundof claim 13 wherein Z is —S—CR₄R₅—, and R_(1d) is H.
 16. A compound ofclaim 12 having the following formula V

where X₁ is C or N; X₂ is CZ_(3a), NZ_(3a), O or S; Z_(3a) is H,hydroxy, optionally substituted alkyl, optionally subsitutedheterocyclo, optionally substituted aryl, optionally substitutedaralkyl, —OZ₆, —C(O)_(q)H, —C(O)_(q)Z_(6a), —Z₄—NZ₇Z₈, or—Z₄—N(Z₁₀)—Z₅—Z₆; n is 1 to 3; and m is zero to
 2. 17. A pharmaceuticalcomposition comprising at least one compound of claim 1 and apharmaceutically acceptable vehicle or carrier therefor.
 18. Apharmaceutical composition of claim 17 further comprising at least oneadditional therapeutic agent selected from anti-inflammatory agents,anti-proliferative agents, anti-cancer agents or anti-cytotoxic agents.19. A pharmaceutical composition of claim 18 wherein the additionaltherapeutic agents are selected from steroids, mycophenolate mofetil,LTD₄ inhibitors, CTLA4-Ig, LEA-29Y, phosphodiesterase inhibitors,antihistamines, or p³⁸ MAPK inhibitors.
 20. A method of treating a Tecfamily tyrosine kinase-associated disorder comprising the step ofadministering to a patient in need thereof, an effective amount of atleast one compound of claim
 1. 21. The method of claim 20 wherein theTec family tyrosine kinase-associated disorder is an Emt-associateddisorder.
 22. The method of claim 21 wherein the Emt-associated disorderis selected from transplant rejection, rheumatoid arthritis, multiplesclerosis, inflammatory bowel disease, lupus, graft vs. host disease,T-cell mediated hypersensitivity disease, psoriasis, Hashimoto'sthyroiditis, Guillain-Barre syndrome, cancer, contact dermatitis,allergic disease, asthma, ischemic or reperfusion injury, atopicdermatitis, allergic rhinitis, or chronic obstructive pulmonary disease.